https://mediasite.med.upenn.edu/mediasite/Catalog/catalogs/2020-bgs-orientation

The lab's research fuses the disciplines of mucosal immunology, microbial pathogenesis and microbial ecology to investigate mechanism of immune homeostasis and protective immunity.
One of the lab’s main research focuses is the pathogenesis of and host response to Clostridium difficile, a bacterium that infects the large intestine following perturbation of the intestinal microbiota and is the leading cause of hospital-acquired infections in the United States.
There four main factors that determine the severity of C. difficile pathogenesis: 1.) The bug itself, (the strain of C. difficile ) 2.) the composition of the Microbiota, 3.) the host’s diet, and 4.) the host’s immune system.
The interactions of these four factors determine severity of disease. In the Abt lab, we take a systematic approach by standardizing three of these factors then modulating the fourth to understand it’s contribution to disease. Using a murine model of C. difficile infection and human clinical samples, our research team investigates immune-microbiota regulation of C. difficile associated disease.

mucosal immunology, microbiota, immunity, infection, Clostridium difficile, host-pathogen interactions

Inborn errors of metabolism (IEMs) are rare inherited disorders of biochemical pathways that occur in approximately 1/1,500 births. For most IEMs, it is not known how the biochemical defect leads to neurologic symptoms. Yet, most patients have significant, untreatable central nervous system (CNS) disease. Our long term goal is to establish a mechanistic understanding of these disorders in order to develop novel therapies that prevent or reverse their neurologic manifestations. Our studies of rare disease patients with inherited disorders of neurochemistry also provide important mechanistic insights into more common neurologic conditions.
Using genetic, biochemical, and electrophysiologic techniques in cells, model organisms, and human subjects, we investigate the mechanisms that drive neurologic dysfunction in patients with IEM. We also evaluate the efficacy of a number of new therapeutic strategies for IEM (including small-molecule, network-directed, and gene therapies). We hypothesize that genetic defects in biochemical pathways alter the development and evolution of electrical circuits in the brain. To improve outcomes in patients with IEMs, therapies will have to correct both the biochemical defect and the secondary circuit-level pathology that directly drives patients’ symptoms.
In addition to our studies of known neurometabolic disorders, we have an active translational research program aimed at identifying and characterizing new genetic disorders. These discoveries often shed light onto pathologic mechanisms that are shared with more common disorders. As an example, we identified a new disorder of AMPA-receptor recycling due to mutations in ATAD1. This work stimulated a targeted therapeutic trial in this rare disease and has motivated others to explore the link between this gene and neuropsychiatric disorders.

human genetics, inborn errors of metabolism, neuroscience, therapy development, translational research

Dr Alexander-Bloch investigates normal brain development and the altered developmental trajectories that lead to mental illness, using a multi-disciplinary approach that integrates structural and functional brain imaging, genomics and clinical phenomics. The lab team's goal is to translate the highly polygenic risk for psychosis and other neurodevelopmental psychiatric disorders into pathophysiologic mechanisms, to inform therapeutic targets and improve risk assessment. Current projects include: 1) Lifespan trajectory models of post-mortem brain gene expression and brain MRI morphological features (n=100,000 scans including shared and open data); 2) Influence of copy number variants and polygenic risk on brain development and psychiatric risk, in the Philadelphia Neurodevelopmental Cohort; 3) Analysis of clinically-acquired brain MRI at CHOP and integration with natural language processing of physician notes from electronic health record; 4) Transcriptome-wide association study of neuroimaging phenotypes in the UK Biobank. Rotation Projects are available within the scope of each of the above projects.

brain imaging, genomics, psychiatry, network science

https://www.research.chop.edu/brain-gene-development-lab

Our lab uses techniques from machine learning, engineering, and systems biology to understand how sleep and molecular rhythms influence physiology in the brain and body.
Work in mice, fish, and flies has shown that daily rhythms modulate the expression of thousands of transcripts, proteins, and metabolites. The influence of sleep and wake, while less well characterized, appears similarly profound.
The translation of these findings to medicine has been limited by our inability to collect time course tissue samples from people, especially from sick patients. Even when genes or proteins are found to cycle with time-of-day or sleep/wake, it is often a daunting challenge to understand how these many changes interact to influence physiology.
We have developed methods to extract rhythmic signals from large human tissue databases. In this way we are trying to “fill in the gaps” regarding human circadian molecular physiology – and the changes that occur with illness. We are also trying to better characterize the importance of these rhythms and understand the different ways that they can be disrupted (disorganized rhythms, de-synchrony at different scales, changes in rhythm strength).
Currently our lab is particularly focused on understanding how molecular rhythms might be disrupted in cancer and neurodegeneration. Working with collaborators we have some new, and unique data sets we want to analyze. We are also gearing up to do some experiments (and are funded to do so) – taking the lab in a bit of a new direction. I am also just interested in new ideas about sleep, rhythms, and biological dynamics.

sleep, circadian rhythms, machine learning, systems biology, bioinformatics, neurodegeneration, cancer

The lab develops machine learning algorithms/tools that
integrate Genomic and Genetic (BigData) to understand/predict RNA processing (alternative splicing, polyadenylation, translation, etc.) as it relates to gene regulation, development, and human disease. We then follow our predictions/hypothesis with experimental verification (we have both dry and wet lab). Much of our work is done in collaboration with specific disease experts across Penn and CHOP, including joint mentorship of students/postdocs. The lab is joint between Department of Genetics and Computer Science. We have PhD students from CAMB/GCB (School of Medicine), and CIS (school of Engineering) as well as professional developers.

Machine Learning, Computational Biology, RNA processing, alternative splicing,

My laboratory studies the epigenetic control of mammalian development with a specific emphasis on genomic imprinting, a phenomenon that results in the parent-of-origin specific expression of a small number of genes. We also study how DNA methylation reprogramming is regulated in the germ line and in early development and how environmental exposure and assisted reproductive technologies can reprogram the embryo, leading to adverse outcomes.

imprinting, mammalian development, DNA methylation, Epigenetics

https://www.med.upenn.edu/apps/faculty/index.php/g20000320/p13534

Our research is directed toward understanding fundamental mechanisms that control the development of the nervous system. We use the Drosophila embryonic CNS and the mouse spinal cord systems to study these mechanisms, with a particular emphasis on the control of axon guidance at the midline. Defects in the formation of midline circuitry can lead to profound deficits in motor control and cognitive abilities. We also have projects focused on the development and assembly of motor neuron circuitry. In particular, we are investigating how the transcriptional programs that specify neuron sub-type identity control the morphogenesis of motor axons and their dendrites.

axon guidance, Drosophila, mouse, neural development, receptor signaling

Elucidating genetic, epigenetic, and biochemical mechanisms that regulate lymphocyte development to promote the establishment of effective adaptive immunity while suppressing autoimmunity and lymphoid malignancies.

lymphocyte development, adaptive immunity, autoimmunity, lymphoid cancers

Thousands of children are suspected to have a genetic disorder but have no diagnosis, even after expert evaluation. Many of these children have yet-undiscovered genetic syndromes, and the Bhoj Lab aims to provide answers to families about their child's medical issues and work toward targeted therapies for genetic disorders. The lab uses advanced sequencing technology to identify these novel syndromes. Two of the syndromes focused on in the lab are caused by disruption of Histone 3.3 (H3F3A and H3F3B) and TBC1 domain-containing Kinase (TBCK).
Histone 3.3 is a replacement histone, and is vital for appropriate cell division, transcription, and many other processes. Somatic variants cause a variety of cancer, including pediatric glioblastoma. The Bhoj Lab described a pediatric neurodegenerative condition caused by germline variants in H3F3A and H3F3B, which both code for Histone 3.3. Using patient cells, mouse models, and iPSC cells, the lab team is learning more about why these genetic variants cause this disease. Their goal is to be able to learn enough about the pathogenesis of the disorder to develop the first targeted therapies for this progressive neurologic disorder.In addition, the lab was instrumental in the discovery of TBC1 domain-containing Kinase (TBCK) as a cause of progressive neurodegeneration in children. Little is known about TBCK, and the lab is learning more about how TBCK works in healthy tissues and contributes to neurodegeneration. The team uses patient cells and model organisms to understand how the loss of this protein disrupts normal neurologic development. Early data suggested the mTOR pathway was downregulated in these patients, and the Bhoj Lab showed that leucine, an amino acid, is a potential targeted therapy. The lab is now working on leucine and related compounds in animal models of the disease with the aim of starting a human trial.

human genetics, translational, neurogenetics, targeted therapeutics

https://www.research.chop.edu/bhoj-laboratory/bhoj-lab-research

The Black Lab is answering the most pressing questions in chromosome biology, such as:
How does genetic inheritance actually work?
How was epigenetic information transmitted to us from our parents?
Can building new artificial chromosomes help us understand how natural chromosomes work?
How are the key enzymes protecting the integrity of our genome specifically and potently activated by potential catastrophes like DNA breaks or chromosome misattachment to the mitotic spindle?

Chromosomes; Epigenetics; Genome Integrity; Structural Biology; Mass Spectrometry; Mammalian Germline; Synthetic Biology

We study how genetic regulatory elements are organized spatially in the nucleus and how transcription programs and chromatin architecture are organized throughout the cell cycle to maintain lineage identity. A major effort in the lab is directed towards understanding the regulation of globin gene expression and developing approaches to perturb globin gene expression to ameliorate sickle cell disease. Our work bridges basic science with preclinical studies. For our studies we combine molecular, genomic, biochemical, and imaging approaches with studies in normal and gene targeted mice.

epigenetics, gene expression, nuclear architecture, globin genes, sickle cell disease, epigenetic and pharmacologic therapeutics, transcription, hematopoiesis

Rotation student would work on investigating the role of genetics on maternal health outcomes using EHR data linked with genetics from the Penn Medicine BioBank.

electronic health records; biobank; genetics; environment; prenatal/perinatal

My lab works on mechanisms of brain aging - trying to understand how the brain can maintain resilience from disease and environmental impacts. We take a genetic approach, and extend to molecular mechanisms, using gene manipulation, sequencing approaches, epigenetics and others. We work in Drosophila, but launch to other systems, including mammalian cells, mouse tissue and human tissue.

brain, aging, neurodegeneration, TBI, RNA modifications

Innovation in Nanomedicine & Drug Delivery
Our goal is to provide solutions to the Achille's heel of drug therapy and the reason most fail in clinical trials: Drugs that are intended to work on one organ or cell type actually distribute all over the body, where they cause off-target side effects that limit the maximal dose and impede therapy. To solve this pervasive problem, we aim to innovate new nanotechnologies and drug delivery tools to massively concentrate drugs at their intended site of action, thus minimizing side effects and maximizing therapy. We design our nanoscale drug carriers using tools from formulation chemistry, bioconjugate chemistry, protein engineering, and computational modeling. We test our technologies in rodent and large animal models, as well as ex vivo human organs, always with the goal of iteratively improving our nanotechnology designs so they can reach patients.
We focus particularly on a very large class of diseases that suffers the most from the drug distribution problem: acute critical illnesses (ACIs), which are diseases that can immediately lead to death or permanent organ dysfunction. ACIs include ARDS (the lung inflammation that kills in COVID-19), stroke, heart attack, sepsis, post-surgical conditions, trauma, and many more.
Since our goal is to get technologies to patients, we believe in the importance of partnering with industry. We have multiple industry partners we work with closely, providing our trainees with industry experience and contacts. We also love entrepreneurship, as the lab's PI, Jake Brenner, has founded 3 funded companies (including one FDA approval), and teaches medical technology entrepreneurship at Penn.
Please join us in the fight, building nanotechnologies to defeat these terrible diseases!

bioengineering, pharmacology, drug delivery, nanotechnology, nanomedicine, biomaterials, computational modeling, ARDS, sepsis, stroke, infectious diseases, inflammation, innate immunity, endothelial, neutrophil

The Burslem lab is interested in developing chemical tools to understand and modulate lysine post-translational modifications, specifically acetylation and ubiquitination. The laboratory is particularly interested in novel pharmacological approaches to modulate post-translational modifications which regulate gene expression and protein stability.

lysine, post-translational modifications, chemical biology, acetylation, ubiquitin

We seek to understand interactions between microbes and humans, and modulate those interactions to improve health. Much of our work involves new method development, today often using deep sequencing and bioinformatics, to gain new information about interactions at the human-microbe interface.
Research in our laboratory has helped nucleate several initiatives on campus, including the PennCHOP Microbiome Program, the Penn Center for AIDS Research Viral and Reservoirs Core, and the new Penn Center for Research on Coronaviruses and Other Emerging Pathogens. Historically projects in the lab have focused on HIV replication, particularly the integration step; the human microbiome in health and disease; and human gene modification using microbial-derived reagents such as viral vectors or CRISPR systems.
Potential rotation projects include the following:
1) In response to the COVID-19 epidemic, our laboratory has pivoted to studies of SARS-CoV-2. Active projects include studies of SARS-CoV-2 viral genomics, and interactions between SARS-CoV-2 and the microbiome of the respiratory tract.
2) Recently our laboratory discovered a new family of human viruses, Redondoviruses, that are the second-most abundant in human airway. Efforts today focus on understanding function of the viral proteins, and developing methods for growing Redondoviruses in culture. Long term, we hope to develop Redondoviruses as vectors for gene transfer.
3) We are studying the human virome in multiple disease states and at multiple body sites. Active projects include studies of the virome in IBD and colonization in early life.
4) We are also following up on discoveries on AAV genomics during gene correction in model vertebrates and in humans with the goal of increasing therapeutic efficiency.
Most of our work involves collaborations with other groups. One and 2 are close collaborations with Ron Collman, 3 is a collaboration with many clinical researchers at Penn, and 4 is a collaboration with Denise Sabatino.

microbiology, microbiome, virome, HIV, AAV, Redondoviruses, next generation sequencing

The Camara lab is focused on the development and application of innovative computational approaches for studying cancer heterogeneity. To that end, we draw ideas from topology, geometry, statistics, physics, and computer science. Combining these approaches with high-throughput single-cell technologies and large-scale population studies, we aim to achieve a more complete understanding of the cell composition and signaling networks of tumors. Our research is organized around three areas of activity: 1) the development of clustering-independent algorithms for the integration and analysis of single-cell multi-omics data, 2) the functional characterization of chimeric antigen receptor (CAR) T cell immunotherapies using single-cell omics approaches, and 3) the study of the cell ecosystem, oncogenic pathways, and immuno-regulatory mechanisms of childhood ependymoma, a rare but devastating type of brain cancer.

pediatric gliomas, CAR T cells, cancer genomics, single-cell multi-omics, computational methods

The Capell Lab seeks to understand how epigenetic and epitranscriptomic mechanisms contribute to disease. By combining the incredible accessibility of human skin with the most cutting-edge epigenetic and epitranscriptomic techniques, we aim to identify novel targets to treat disease.

Epigenetics, Epitranscriptomics, Skin, Cancer, Gene Regulation

We use a cutting-edge technique called "cryo-electron tomography" to visualize molecular structures directly inside frozen cells to understand how they conduct cellular functions.

Structural biology, imaging, cryo-EM, microscopy, microbiology, cell biology, biophysics

Metastasis, the spread of cancer from primary tumor sites to distal organs, is the cause of 90% of deaths from cancer. Brain metastasis is an unmet clinical challenge due to the increasing incidence in recent years. Yet, brain metastasis suffers from a dearth of experimental models, mechanistic insights, and research in general.
Metastatic outgrowth at distal organs requires the complex interplay between cancer cells and the stromal cells, a process commonly referred to as “seed and soil hypothesis”. The ‘soil’ (brain microenvironment) not only decides the outgrowth of metastatic cancer cells, but also contributes to therapy resistance. Meanwhile, the ‘seed’ (invaded cancer cells) modify the surrounding brain cells. Our angle to study metastasis is to focus on the complex crosstalks between cancer cells and in brain cells. The ultimate goal is to overcome this challenge by identifying prognostic markers and novel therapeutic targets.
Our lab in The Wistar Institute is taking a multidisciplinary approach, spanning molecular and biochemical analyses combined with sophisticated in vivo imaging and live animal studies. In project 1, we focus on cancer-microenvironment interactions in the brain, aiming to identify new therapeutic targets to treat brain metastases. In project 2, we study how primary breast tumors remotely prime the brain microenvironment for metastatic outgrowth, aiming to identify markers/targets to predict and prevent brain metastases. In project 3, we are using powerful imaging techniques to observe brain metastatic process in the brain, in order to optimize the therapeutic window and efficacies for brain metastasis treatments.

Brain metastasis, Tumor Microenvironment

We use a combination of computational and bench-based techniques to elucidate mechanisms underlying neurodegenerative disease. A frequent starting point is human-derived materials, stored in a biobank managed by our lab (with blood and CSF from >6000 unique individuals with Alzheimer's Disease, Parkinson's Disease, ALS, or frontotemporal dementia). We use these materials in "omic"-scale screens to identify leads for mechanistic follow-up in cellular and animal model systems.

Neurodegeneration, genetics, genomics, biomarker

Good quality sleep is essential for our mental health. Patients suffering from chronic stress or psychiatric disorders are often plagued by disrupted or insufficient sleep, and disturbed sleep has been shown to increase the risk of developing psychiatric disorders suggesting that the neural circuits controlling sleep are tightly inter-connected with circuits involved in emotional regulation and psychiatric disorders.
The goal of our lab is to identify the molecular and neural mechanisms controlling sleep and sleep homeostasis, and to understand how these are interconnected with the neural circuits regulating emotional states in health and disease. To accomplish this, we employ a multi-disciplinary approach:
(A) Optogenetic and pharmacogenetic manipulation to examine the impact of cell type specific manipulation on sleep and behaviors. (B) In vivo electrophysiology, deep brain imaging and fiber photometry to observe dynamic changes of neural activity in sleeping and behaving mice. (C) Circuit mapping using viral tools to comprehensively identify the synaptic inputs and outputs of a genetically defined neural population. (D) Gene profiling to identify novel molecular markers of sleep neurons and to understand how the genetic signature of newly identified sleep neurons are influenced by behaviors.

Sleep, stress, emotion, neurodevelopment disorders, psychiatric disorders, systems neuroscience, optogenetics, calcium imaging, in vivo electrophysiology

The Conine lab is interested in how RNAs present in sperm are capable of transmitting non-genetic information to their progeny, influencing offspring phenotype. This includes, 1) how small RNAs regulate gene expression in the male germline to support spermatogenesis and fertility, 2) how small RNAs are packaged into mature sperm, 3) how RNAs transmitted during fertilization are able to regulate early embryonic gene expression and development, and 4) how this regulation can alter developmental programs to produce a non-genetically inherited phenotype. The lab utilizes a combination of state-of-the-art genomic, molecular biology, and assisted reproduction techniques across multiple model systems including mice, embryonic stem cells, and C. elegans to understand these questions.

epigenetic inheritance, RNA, sperm, embryo

The Cremins Lab focuses on higher-order folding of the genome and how epigenetic marks work through long-range regulatory mechanisms to govern neural cell fate in the mammalian brain. Much is already known regarding how transcription factors and epigenetic marks work in the context of the linear genome to regulate neuronal development and function. Yet, severe limitations still exist in our ability to apply this knowledge to engineer neuron fate at will or correct brain diseases in vivo. The overarching goal of the Cremins lab is to obtain a detailed mechanistic understanding of how the genome is folded and reconfigured during neural lineage commitment and synaptogenesis and how these folding patterns influence the specificity, maturation, and pruning of neuronal connections in healthy mammalian brain development. We also study how the genome is misfolded in neurodegenerative disease and we develop tools to engineer 3-D genome folding on demand. Recently, we discovered that short tandem repeat sequences which grow unstable in a cohort of 30 trinucleotide expansion disorders are uniquely localized to a precise chromatin architecture pattern which is subsequently disrupted in patients with Fragile X Syndrome. We have also built a novel light-activated dynamic looping (LADL) tool to engineer genome folding on demand with blue light. Our long-term goal is to re-engineer genome architecture defects to attenuate or reverse pathologic transcriptional silencing in debilitating neurodevelopmental and neurodegenerative diseases.

Hi-C, 3D genome, neuroepigenetics, epigenetics, neurodegenerative disease, Alzheimer's, Fragile X Syndrome, chromatin, neuroscience

katedavis@pennmedicine.upenn.edu

Dr. Davis’ research centers around utilizing both the advancing fields of invasive neurophysiology and neuroimaging to better localize epileptic networks in medication refractory epilepsy patients. The lab focuses on using quantitative analyses and network science to localize epilepsy networks with the goal to enable epileptologists to better localize epileptic networks and assign individual patients to the most efficacious therapy, for example, seizure control devices, resective surgery, or continued medical management.

epilepsy, imaging, intracranial EEG, network neuroscience

BMB, CAMB (MVP), GCB, IGG, NGG, PGG

The Machine Biology Group seeks to expand nature’s repertoire to build novel molecular tools and devise therapies that nature has not previously discovered. We are developing tools and medicines by means of computers that will replenish our current antibiotic arsenal, engineer the microbiome and provide novel approaches to study and control brain function and behavior. To achieve this, we merge principles from synthetic biology, microbiology, chemistry, physics, engineering and computer science. We have developed new technologies ranging from genetic and pattern-recognition algorithms, structure-guided rational design, and engineered synthetic peptides to combat bacterial infections, each with broad applications in medicine and biotechnology.

synthetic biology, computational biology, microbiology

Iron is essential for life. In physiologic conditions, iron can accept or donate electrons, serving as a cofactor in chemical reactions as fundamental as DNA synthesis and energy metabolism. But iron’s very source of utility is also its source of toxicity. Excess iron can trigger oxidative stress and cell death. For the past two decades we have studied the role of iron in age-related macular degeneration. We use retinal cell culture, transgenic/knockout/conditional knockout mice, human post mortem tissue, cell sorting, transcriptomics, pharmacologic and gene therapy interventions in preclinical models.

neurodegeneration, oxidative stress, retina, eye, iron, transport, mouse model, transcriptomics

EISENLC@PENNMEDICINE.UPENN.EDU

Processing and presentation of viral antigens to CD4+ and CD8+ T cells, T cell activation and memory

antigen processing and presentation, CD4+ T cells, CD8+ T cells, influenza, sendai, ectromelia, salmonella, HIV, SARS-CoV-2

http://pathology.med.upenn.edu/department/people/725/laurence-eisenlohr

We are interested in the neural mechanisms of hearing and vocal communication. We approach this with a mix of neural recording and behavior in non-human primates.

auditory cortex, neural coding, vocal communication, social behavior

Dr. Ertl's research centers on developing vaccines for an array of diseases and conditions—including AIDS and some forms of cancer—not typically considered to be treated using this approach. These vaccines aim to protect against future infections and look to create new therapies for diseases already affecting people.
Test vaccines to hepatitis V virus or COVID-19, Develop and test an optimised version of the glycoprotein D checkpoint inhibitor which prevents binding of the B and T lymphocyte attenuator to the herpes virus entry mediator which dampens T cell response at an early stage of activation

Vaccines, COVID-19, chronic HBV infection, vector development, immune responses, T cells, tumor microenvironment

The research interests of our laboratory lie at the intersection of image-guided interventions, cancer biology and molecular imaging. Our research is motivated by clinical deficiencies in interventional radiology and seeks to go from bedside-to-bench and back again to further diagnosis and treatment.
Interventional oncology represents the fourth arm of cancer therapy offering locoregional treatment approaches for a variety of malignancies. These approaches apply minimally invasive procedures to target cancer using percutaneous or endovascular techniques through direct targeting of the tumor and its microenvironment. Our research seeks to leverage these techniques in order to study the influence of the tumor microenvironment on subpopulations of cancer cells as well as on the interactions of stromal cells within the tumor in order to develop novel imaging approaches and advanced therapeutics. The characterization of these phenomena will enable the development of more precise image guided interventions to improve outcomes in cancer patients. This research requires the integration of several disciplines including molecular biology, bioengineering and imaging physics. On-going projects in the lab emphasize this integration:
Metabolic Imaging of Cellular heterogeneity in Cancer: This project focuses on the development of a high throughput platform to enable metabolic imaging paradigms that can distinguish between cell types and among cancer cell states in vivo.
Targeting the Metabolic Stress Response in Hepatocellular Carcinoma This project focuses on the characterization of the molecular mechanisms used by hepatocellular carcinoma (HCC) cells to survive ischemia induced by transarterial chemoembolization (TACE), the most commonly used treatment for HCC in the United States.

hepatocellular carcinoma, locoregional therapy, cancer metabolism, precision medicine, molecular imaging, hyperpolarized imaging

The long-term goal of our research is to identify the neuronal circuits and neuronal codes that support hearing and auditory memory and learning in complex acoustic environments. Auditory perception is shaped by the interaction of sensory inputs with our experiences, emotions, and cognitive states. Decades of research have characterized how neuronal response properties to basic sounds, such as tones or whistles, are transformed in the auditory pathway of passively listening subjects. Much less well-understood is how the brain creates a perceptual representation of a complex auditory scene, i.e., one that is composed of a myriad of sounds, and how this representation is shaped by learning and experience. Over the last six years, our laboratory has made transformative progress in the quantitative understanding of neuronal circuits supporting dynamic auditory perception, through a combination of behavioral, electrophysiological, optogenetic and computational approaches. Specifically, we have:
(1) Discovered a novel role for the auditory cortex in learning-driven changes in auditory acuity;
(2) Discovered a novel intra-cortical circuit supporting adaptation to temporal regularities in sounds;
(3) Identified computational mechanisms for encoding of complex sounds in the auditory cortex;
(4) Identified neural mechanisms underlying development of perception of environmental sounds and speech perception.
​With these findings, our laboratory is positioned to make a breakthrough in the computational and theoretical understanding of audition over the next few years. Whereas the specific research projects in the laboratory focus on investigating distinct circuits involved in specific auditory functions, our aspiration is to develop a comprehensive computational framework for understanding neuronal dynamics in perception and memory. Our focus on the function these circuits in audition will pave the way for understanding processing across sensory modalities and brain regions.

auditory cortex, sensory processing, neuroscience, computational neuroscience, systems neuroscience, imaging, electrophysiology, behavior, hearing

mattgood@pennmedicine.upenn.edu

The Good laboratory is interested in how cells sense and regulate their dimensions and the consequences of cell size variation on normal and pathophysiological cell functions. To address the impacts of cell size alteration, we focus on early embryo development, a period in which cells rapidly reduce in cell size due to cell division in the absence of growth (Chen et al, Dev Cell 2019). Additionally, we reconstitute cytoskeletal processes and organelle assembly inside synthetic cell-like compartments with tunable size (Good et al, Science 2013, Caldwell et al, Biochemistry 2018). The broader significance of our research lies in the fact that improper regulation of cell and organelle size are linked to human developmental disorders, cellular senescence and cancer progression. We are also interested in mechanisms that control the spatial organization and insulation of biochemical reactions within a cell. In particular we are interested in phase separation of disordered proteins to form membraneless organelles. We characterized the sequence determinants of phase separation for the RGG domain from Laf-1, a key protein in the assembly of P granules (Schuster et al, PNAS 2020). Leveraging this information, we constructed a synthetic membraneless organelle platform (Schuster et al, Nature Comm 2018), and developed optogenetic and optochemical tools to regulate organelle assembly (Reed et al, ACS Syn Biol 2020) (Caldwell et al, Biochemistry 2018). The versatility of the system enables modular recruitment of client or cargo proteins to a designer organelle inside the cell to gate cell functions. Our ultimate engineering goal is to modulate the properties of P granules and other protein condensates in living cells and embryos to dynamically control cellular decision-making.

Genome Activation, ZGA, Cell Size, Morphogen Gradients, Optogenetics, Membraneless organelles, P Granules

One research focus of the lab is centered on studying the mechanisms of subglottic stenosis profiling patients samples in terms of their airway microbiome, transcriptomics, and proteomics. Samples include tissue biopsies for extraction of laryngeal fibroblasts to study the mechanism of the disease and test potential candidate therapeutics identified.
The second area of research, applies tissue engineering and regenerative medicine approaches to create tissue substitutes to enlarge the stenotic airway. We focus primarily on cartilage substitutes for airway, ear, and nose reconstruction.
An interesting project within this research focus is studying how stem cell differentiation can be enhanced by defined local structures.
Finally, we use organ-on-chip approaches to study the mechanisms of osteoarthritis in the joint.

regenerative medicine, tissue engineering, microbiome, airway, musculoskeletal

I have been conducting human genomics research for over 20 years. The highlights of my career are the discovery of the polymorphic Sp1 site in the COL1A1 gene and its association with osteoporosis, the identification of variation in the TCF7L2 gene playing a key role in conferring type 2 diabetes risk and providing leadership in an international genetics effort to characterize genes influencing birth weight and common childhood obesity risk. I have also previously played a role in uncovering genes involved in other traits, including cleft lip with or without palate, scoliosis, inflammatory bowel disease, autism, ADHD, head circumference, intracranial volume, myocardial infarction, pediatric eosinophilic esophagitis, type 1 diabetes, asthma, multiple sclerosis and neuroblastoma.
As a Director of the Center for Spatial and Functional Genomics at the Children's Hospital of Philadelphia, my current work primarily involves investigating disease genomics with a specific focus on pediatrics. Utilizing high-throughput genotyping and sequencing technologies, combined with statistical and bioinformatic approaches, my goals include unraveling genomic puzzles related to childhood obesity, pediatric bone strength determination, early onset diabetes and cancer. These phenotypes are known to be strongly determined by genetic factors; however, resolving genomic contributors to such complex phenotypes in adults has been impeded by interaction with strong environmental factors. Distillation of the genomic architecture in these complex traits should be easier to determine in children, where the relatively short period of their lifetime limits the impact of environmental exposure. Given the global prevalence of such diseases, prevention of these disorders and their serious complications must be addressed in order to reduce individual morbidity and the economic burden on society.

GWAS, genomics, ATAC-seq, chromatin capture, sequencing, complex traits

https://www.med.upenn.edu/apps/faculty/index.php/p8140245

The Greene Lab is a team of researchers dedicated to answering important questions in biology and medicine with computation. We focus on bringing together publicly available “big data”, developing new computational methods to analyze that data, and creating tools to put those resources into the hands of every biologist.

machine learning, genomics, public data

In the central nervous system, oligodendrocytes synthesize myelin as an extension of their plasma membranes. This myelin wraps axons and facilitates rapid and efficient conduction of nervous impulses as well as axonal nourishment and protection. Destruction of myelin through injury, such as birth injury leading to cerebral palsy, or disease, such as multiple sclerosis or HIV, causes loss of motor and cognitive function. Oligodendrocyte precursors and stem cells remain in the CNS following the pathology and are potentially capable of forming mature oligodendrocytes and then myelin. However, their maturation is severely limited. Reasons for this, as we and other have identified, include the presence of signaling factors and processes such as the integrated stress response, oxidative stress, and lysosomal dysfunction that either inhibit oligodendrocyte maturation or even cause cell death. We study these pathologies in tissue culture as well as in disease models. One active project in the lab is oligodendrocyte dysfunction in HIV-associated neurocognitive deficits (HAND). Almost half of HIV+ individuals exhibit some form of cognitive and behavioral deficits even if their viral load is properly controlled antiretroviral drugs and one of the most consistent findings in these individuals is white matter and myelin loss. We, in collaboration with the Jordan-Sciutto lab, have found that this is due to the indirect effects of the virus in the nervous system as well as off-target effects of select antiretrovirals. These studies have identified cellular mechanisms important for myelination which could be targeted for therapy. Other studies in our lab examine white matter loss in perinatal injury, especially hypoxia/ischemia and studies on multiple sclerosis. Current basic biology studies in the lab include the role of lipid generation in developmental myelination and remyelination and the role of lysosomes in oligodendrocyte maturation.

myelin, oligodendrocytes, HIV, antiretrovirals, perinatal white matter injury, multiple sclerosis

https://www.med.upenn.edu/apps/faculty/index.php/g324/p6243

We use multidisciplinary approaches to study how cells segregate their chromosomes during cell division. Current projects in the lab use in vitro reconstructions and computer simulations to investigate interactions between kinetochore proteins and microtubules. Possible rotation projects include 1) Brownian dynamics simulations of microtubule-binding proteins and their translocation along microtubules; 2) reconstructions of microtubule-attachments sites using DNA origami technology and single molecule TIRF microscopy.

cell division, advanced microscopy, computer simulations, in vitro motility assays

The Grohar lab utilizes a bench to bedside approach to therapeutic development for pediatric solid tumors. Our goal is to identify novel therapeutic vulnerabilities at the interface of transcription and epigenetics and effectively translate these therapies to patients. The unifying principle is that improvement in outcomes for patients with pediatric solid tumors can only come through the development of mechanistically driven studies that target the driver oncogene of these cancers. The challenge is that many of these tumors are driven by “undruggable targets” such as transcription factors. Therefore, we employ unbiased approaches to identify candidate compounds/targets and fundamental mechanistic biology and genomics to dissect their mechanism of action. We use the identified mechanism to improve the therapies either with second and third-generation inhibitors with improved properties or synergistic combination therapies. More recently, we have focused on understanding the cellular context in which these therapies will be tested in patients in order to further improve the translation of these therapies. Finally, we have a clinical trial opening in the next month that will aid in the development and testing of new therapies.

Ewing sarcoma, transcription factors, EWS-FLI1, sarcoma, epigenetic

Our group focusses on the genetics and phenotypes of rare neurological disorders in children, using bioinformatic and data science approaches. We use novel technologies for variant interpretation and computational methods to link large-scale phenotype data including electronic medical record data with genomic information. Overview of projects at "The Phenotyping Gap" https://www.youtube.com/watch?v=_LLQYNv9sgg

bioinformatics, genomics, electronic medical records, computational phenotypes, exome sequencing

We observe developmental processes and attempt to understand recreate them with engineering tools. One particularly inspiring model system for us is the developing kidney, which undergoes a beautiful branching morphogenesis process. We aim to move beyond kidney organoids to address large-scale patterning of iPSC-derived nephrons in engineered tubule networks. We're also studying fundamental aspects of tubule elongation and avoidance in the kidney, and creating single-cell analysis approaches.

developmental engineering, kidney, collective cell behavior, guided differentiation, 4D imaging

In the Penn Digital Neuropathology Lab (DNPL), we use a multidisciplinary approach merging techniques in "wet-lab" based histopathology of human brain tissue with "dry-lab" based image analysis and bioinformatics tools with the overarching goal of improving our understanding of brain-behavior relationships and the antemortem diagnosis of neurodegenerative disease.

neurodegeneration, neuropathology, biomarker, image analysis, connectomics

Viruses are evolutionarily perfected machines. They determine ways to evade, overcome and/or sidestep our immune system through endless battle of high-risk trial and error. The study of viral infection mechanisms, or how viruses interact with the host immune system, can thereby aid in the discovery of immune control. We are interested in understanding immune responses elicited by emerging viral pathogens. Specifically, from the host perspective, we are interested in understanding immune control regulation at the maternal-fetal interface and in the nervous system since both of these regions require tight immune control to prevent immunopathology. From the pathogen perspective, we are interested in understanding how emerging viruses themselves have evolved mechanisms to silence host immune responses.

The Kalish laboratory studies the interface between epigenetics, growth dysregulation, and cancer. We focus on Beckwith-Wiedemann syndrome (BWS), an epigenetic overgrowth disorder that affects multiple organ systems (include liver, kidney, pancreas, and tongue). We run the international BWS patient registry and biorepository and have clinical data and samples from hundreds of patients with BWS. The current projects in the laboratory include: 1) using the first human cell-based model of BWS to study the pathways involved in overgrowth and the transition to cancer; 2) genome-wide evaluation at the genomic and epigenomic level using matched affected and unaffected tissue samples through a variety of techniques; and 3) mechanistic exploration of dysregulated pathways leading to overgrowth and cancer in organoid models. As a translational research group, we focus on the intersection between clinical and molecular data to work towards targeted treatment for patients with BWS.

epigenetics, cancer predisposition, hepatoblastoma, Wilms tumor, Beckwith-Wiedemann Syndrome, organoids, translational research

Our work investigates the regulation and function of sleep during brain development. We have established the fruit fly Drosophila as a powerful model for studying basic mechanisms of sleep neurobiology in early life. We have defined circuits in the young adult fly brain that control sleep maturation, and ongoing efforts include large-scale screens to identify genes regulating sleep during the juvenile critical period. We have also demonstrated a sleep state in Drosophila larvae. This platform has opened new avenues to study the genes and circuits regulating sleep at an early neurodevelopmental time period. We have multiple available projects that aim to determine how sleep disturbances in early life are linked to neurodevelopmental disorders, like autism. In addition, we have funded projects studying the development of social behaviors in the context of neurodevelopmental disease models.

drosophila, sleep, social behaviors, autism, development, synapse

While we conventionally think of genomic DNA as a simple polymer of A's, C's, G's, and T's, the chemistry of the genome is in fact far more interesting.
The Kohli laboratory focuses on DNA modifying enzymes and pathways that provide an added layer of complexity to the genome. These enzymes can be involved in the purposeful introduction of mutations or in the chemical modification of nucleobases, making DNA into a remarkably dynamic entity. Many of these processes are at the heart of the battle between the immune system and pathogens, or central to epigenetics. An understanding of their biological activities and their chemical mechanisms can allow them to be harness as biotechnological tools to characterize or alter the genome.
• Epigenetics: Cytosine Methylation and Demethylation; Novel Epigenomic Sequencing Technologies
• Immunology: The Origins of Antibody Diversity; Harnessing Mutators for Targeted Genome Editing
• Infectious Diseases: Targeting Pathogen Pathways that Promote Evolution and Antibiotic Resistance

Epigenetics, Antibiotic Resistance, Genome Engineering, Bacteria, DNA Methylation,Antibody Maturation,

My research group develops statistical and computational methods for shotgun metagenomics data and applies these methods for studying gut microbiome and various human diseases, including Crohn's disease, childhood development, lung injury, etc. This rotation project will focus on developing machine learning methods to identify and quantify all the biosynthetic gene clusters (BGCs) in microbial genomes and in metagenomic samples. We will investigate the features of the verified about 2000 BGCs and apply deep learning methods to identify other BGCs in the known microbial genomes (6000 genomes). We will explore deep learning methods and statistical segmentation to predict new BGCs. We will next apply the models for shotgun metagenomic data sets to quantify the BGCs for each sample and then associate the BGCs to clinical variables. The rotation will involve uses of existing bioinformatics tools (e.g., metagenome assembly, antiSMASH), developing new statistical methods (RNN and segmentation methods) and analyzing microboiome data sets.

Biosynthetic gene clusters, deep learning, machine learning, statistics, microbiome, metagenomics

Project 1: Impact of bone morphogenetic protein (BMP) receptor signaling on mast cell responses. Inflammatory bowel disease affects millions of people in the United States, and intestinal fibrosis is a major complication of uncontrolled inflammation. Mast cells are an integral part of inflammatory responses that are essential for optimal wound healing and tissue repair. Mast cells have high expression of BMP receptor 2 on their cell surface, and this expression distinguishes them from other immune cell types including basophils. However, the function of this receptor is unknown in mast cell biology. We have discovered that BMP receptor signaling powerfully reduces cytokine production from mast cells following an inflammatory stimulus, without affecting degranulation. We hypothesize that BMP receptor signaling regulates inflammatory responses in mast cells, and that BMP receptor signaling can be targeted for modulation of mast cell responses to inflammatory stimuli. The aims of this project are to investigate the impact of BMPR2 signaling on colitis and endotoxemia, and to dissect the crosstalk between substance P and BMP signaling in mast cells, focusing on therapeutic approaches that could decrease fibrosis in inflammatory bowel disease, using mast cell-specific deletion of BMPR2.
Project 2: SARS-CoV-2 infection of housecats. To date, SARS-CoV-2 has infected multiple dogs and cats worldwide, presumably via spillover infection from humans. However, it is unknown whether SARS-CoV-2 can spread between pets or if they can serve as a reservoir of infection for people. This study will investigate the ability of SARS-CoV-2 to infect feline primary intestinal epithelial cells in 2D organoid culture, compared to human cells, and will be performed alongside a collaborative project which will provide community SARS-CoV-2 testing in cats to study factors associated with naturally occurring infection in cats.

mast cell, inflammatory bowel disease, intestinal organoid, SARS-CoV-2, bone morphogenetic protein

https://www.vet.upenn.edu/research/centers-laboratories/research-laboratory/lennon-laboratory

I work on control of diseases in cities. Main lab is in Arequipa, Peru. Philly lab is virtual. Currently working on modeling evictions in Philadelphia and effect on Covid. Trying to keep surveillance up for Chagas disease vectors via virtual inspections. Looking for students with computational interests, Spanish, or both. Must be ok working in a larger team between Peru and Philly.

Post-transcriptional RNA regulation encompasses critical steps of gene regulation and contributes to the enormous regulatory and functional diversity of human cells. My lab studies the roles of RNA processing and modifications in human health and disease. We focus on two types of prevalent RNA modifications with broad impact on gene activity and function: adenosine (A)-to-inosine (I) RNA editing, and N6-methyladenosine (m6A) RNA methylation. By combining technology development, transcriptome profiling, and biochemical assays, we seek to elucidate the landscape and functions of RNA modifications in normal and diseased states. For example, my lab developed a sensitive method for profiling m6A modifications using limited amount of RNA materials. Using this method, we generated a comprehensive catalog of m6A RNA methylomes for 56 human tissues covering all major organ systems. Furthermore, we identified thousands of tissue-specific m6A sites in the human brain, and demonstrated that genetic variants at these brain-specific m6A sites contribute to the variation of brain gene expression within human populations.
A second focus of my lab is to develop microfluidics-based single-cell technologies for biomedical applications. We have developed a highly versatile microfluidics single-cell platform, in which we use custom fabricated microfluidic chips tailored towards specific applications. We have also developed an automated real-time image acquisition and analysis program, as well as a droplet control program. This provides unique advantages over commercial single cell platforms such as 10x genomics, and enables a wide range of applications that require fluorescent imaging and molecular tagging. We use this platform for three main applications: single cell long-read Nanopore RNA sequencing, to elucidate mRNA isoform complexity in single cells; single cell cross-linking immunoprecipitation sequencing (CLIP-seq), to examine the heterogeneity of protein-RNA interactions in complex cell populations; T cell activity screening and sequencing, to isolate and characterize antigen-reactive T cells for the development of cancer immunotherapy.

RNA modification, transcriptomics, single cell technology, microfluidics

The skeleton is integral to a mammalian body, but skeletal biology is under studied. Whereas congenital skeletal diseases can be devastating in children, aging-related bone and joint ailments exact a heavy toll on the well being of elderly adults. To tackle those problems effectively requires a fundamental understanding of the various cell types that constitute the skeleton, for example the bone making osteoblasts and their precursors commonly known as the mesenchymal stem cells. Besides their intrinsic biology, bone cells are also known to communicate with other cell types or organs in the body, best known among which are local interactions with bone marrow fat cells and blood vessels, as well as long range actions on the kidney in the regulation of phosphorus homeostasis. Our lab is interested in studying not only the development and regeneration of bone cells, but also their cross-talk with other cell types. A particular focus is on cell metabolism as a nexus for cell fate and activity regulation by growth factors and also in response to aging or diabetes.

development, regeneration, mesenchymal stem cells, bone, metabolism, diabetes

https://www.med.upenn.edu/apps/faculty/index.php/g275/p9165367

My lab is interested at molecular and cellular mechanisms underlying pain, itch, and touch sensation. We work with peripheral nerves as well as the central circuits. We use a combination of mouse genetics, optogenetics, virus tracing, behavior assays (we develop novel behavior assays using advanced computer imaging techniques), slice and in vivo recordings, and primary human tissues.

pain, itch, touch, molecular receptor, neural circuit, behavior assay, human tissue, peripheral nerve

minghong@pennmedicine.upenn.edu

We are interested in how the brain perceives sensory information and responds appropriately using the mouse olfactory system as a model. Rodents primarily use olfactory cues to guide their behaviors (e.g., locating food, communicating with conspecifics, and avoiding danger). Odor detection relies on a large family (~1200 in mice) of G-protein coupled odorant receptors (ORs) expressed in olfactory sensory neurons (OSNs) in the nose. OSNs transmit sensory information to the olfactory bulb (the first relay station in the brain), which projects to several olfactory cortical and subcortical regions. Some OSNs serve dual functions as odor detectors and mechanical sensors, thus the olfactory system carries both the odor information and nasal breathing signal into the brain. Our current investigation focuses on how the olfactory system interacts with non-olfactory regions (e.g., the prefrontal cortex and striatum) to influence the brain activity and behavioral output. Since olfactory dysfunction is manifested in neuropsychiatric and neurodegenerative disorders, we are also interested in analyzing the olfactory system and related circuits in diseased states.

olfaction; nasal breathing; brain rhythms; behavior; prefrontal cortex; striatum

My laboratory seeks to understand the molecular mechanisms leading to the formation of lysosome-related organelles (LROs) – cell type-specific organelles of the endolysosomal system – and how these mechanisms go awry in disease. We aim to understand how cell type-specific components contribute to LRO function and the intracellular membrane trafficking pathways that target these components to LROs. These pathways are disrupted in a group of genetic diseases that are collectively referred to as the Hermansky-Pudlak syndromes (HPS). By studying the biogenesis of melanosomes – the melanin-producing LROs within skin melanocytes and eye pigment cells – we and our collaborators have positioned the products of HPS-associated genes within two pathways of membrane protein transport from early endosomes to newly forming melanosomes and one retrograde pathway from melanosomes. Ongoing studies are detailing specific functions for these gene products and their interactors in anterograde and retrograde transport of melanosomal contents. In addition, we aim to understand how melanosome function is impacted by specific proteins within melanosomes, including transmembrane transporters, such as OCA2 and SLC45A2 that are defective in patients with oculocutaneous albinism, and PMEL, a functional amyloid protein that forms the matrix underlying melanin. Recently we have been collaborating with Sarah Tishkoff in the Dept. of Genetics to define the function of genes associated with skin pigmentation differences in African populations. Analyses of one such gene, MFSD12, suggest that lysosomal function impacts melanogenesis in as yet unknown ways. With collaborators we have extended our analyses of LRO biogenesis to other systems, including dense and alpha granules in platelets and megakaryocytes, lamellar bodies in lung epithelial type II cells, and phagosomes in dendritic cells. These organelles are also targeted in different forms of HPS, and we are applying the models that we have developed in melanocytes to probe HPS gene function in these other cellular systems.

Membrane trafficking, subcellular organelles, pigmentation, platelets, dendritic cells, lysosomes, endosomes, Golgi, melanosomes, albinism

My laboratory studies the molecular mechanisms of (1) protein post- and co-translational modification with a particular focus on protein acetylation, (2) enzyme signaling in cancer and metabolism, and (3) epigenetic regulation. The laboratory uses a broad range of biochemical, biophysical and structural research tools (X-ray crystallography and cryo-EM) to determine macromolecular structure and mechanism of action. The laboratory also uses high-throughput small molecule screening and structure-based design strategies to develop protein-specific small-molecule probes to interrogate protein function and for preclinical studies.

Epigenetics, Protein acetylation, MAPK signaling, Metabolism, Structural Biology, Enzymology, Inhibitor Development

https://www.med.upenn.edu/apps/faculty/index.php/g20001500/p20660

Gene expression is regulated by a complex choreography of highly dynamic events, including the binding of transcription factors to non-coding regulatory regions of the genome, regulation of chromatin topology, and the assembly of large macromolecular complexes, all of which occur in the crowded nuclear environment. Our understanding of these dynamic processes has largely been driven by approaches that provide population averaged and static snapshots which have delivered remarkable insights, but are inherently ill suited for elucidating processes that vary greatly in space and time. Comprehending the myriad mechanisms that are at play in regulating gene expression and the role of nuclear organization in this regulation requires technological and theoretical approaches that bridge spatial scales from molecular to organismal and temporal scales from milliseconds to days.
We use and develop advanced imaging technologies and biophysical modelling, along with genomics, and gene editing to quantitatively probe the dynamics of how transcription is regulated during early development and how these dynamics both shape and are shaped by nuclear organization. Using these technologies we are able to probe scales ranging from single-molecule interactions to gene expression patterns at the embryonic scale. These datasets provide a unique perspective on how stochastic and transient interactions at molecular scales give rise to precise patterns of cell-fates during early embryonic development.
Our vision is to utilize quantitative data in combination with mechanistic modelling to develop new strategies to specifically manipulate nuclear organization and transcriptional regulation to achieve desired phenotypes. The insights gained through these projects will not only lead to an improved understanding of one of life’s fundamental processes, transcription, but will also be applicable to the plethora of diseases which have a basis in the misregulation of gene expression.

single molecule imaging, transcription, embryo, development, drosophila, light-sheet microscopy, intrinsically disordered proteins, nuclear organization, super-resolution microscopy

The overarching goal of my research is understand human health and disease in order to improve prevention and treatment. My fundamental assumption is that human health is a complex adaptive system determined by many interacting biological and environmental factors which interact and are dynamic in time and space. A major focus of the lab is on the development, evaluation, and application of artificial intelligence and machine learning algorithms for identifying combinations of biomarkers which are predictive of health-related outcomes. Our recent work has largely focused on automated machine learning algorithms (AutoML). We work with genomics data and clinical data from the electronic health record and study a wide range of common diseases including cancer, cardiovascular disease, infectious disease, and neuropsychiatric disease.

artificial intelligence, bioinformatics, biomedical informatics, complex systems, computational biology, genetics, genomics, electronic health records

The Ortiz-Gonzalez Lab focuses on translational neuroscience, fueled by the belief that there is much neurobiology to learn from patients with rare genetic disorders that disrupt normal neurodevelopment. The lab is particularly interested in whether mitochondrial dysfunction can be a common underlying mechanism in rare pediatric neurodegenerative disorders.

Pediatric Neurodegeneration, Mitochondrial dysfunction, autophagy/mitophagy

A central question in physiology is how different organs communicate with each other to maintain whole-organism homeostasis. Past research has revealed that non-glandular organs such as adipose tissue, liver, and skeletal muscle can secrete hormones that regulate whole-body metabolism. In contrast, little is known about heart-derived hormones save for ANP and BNP, each discovered over 30 years ago.
We recently discovered that Growth Differentiation Factor 15 (GDF15) is a new heart-derived hormone. Circulating GDF15 acts on the liver to inhibit growth hormone signaling and body growth. Plasma GDF15 is increased in children with concomitant heart disease and failure to thrive (FTT). Our results explain a well-established clinical observation that children with heart disease often develop FTT. More importantly, these studies reveal a new endocrine mechanism by which the heart coordinates cardiac function and body growth.
Plasma GDF15 was recently shown to be elevated in patients with various heart diseases and is associated with increased morbidity and mortality. However, how GDF15 is increased in heart disease remains unclear. We studied this clinically important question and identified the whole gene regulatory network that induces GDF15 transcription in heart disease, using massively parallel single-nucleus RNA-Seq (~20,000 nuclei). This study also revealed for the first time the organ composition, cell type, and heterogeneity in normal postnatal, developing mouse heart, and the profound changes of transcriptional landscape of every cell type in the disease state. In addition, we identified the key enzymes that process GDF15 pro-hormone into its mature form.
We are continuing our research in this new area which we call cardiac endocrinology. We use a combination of technologies from single-cell genomics, molecular and cell biology to animal models. We welcome students and fellows to join our group!

Metabolism, Single-cell Genomics, Cardiac Endocrinology, Heart Biology & Disease,

https://www.med.upenn.edu/apps/faculty/index.php/g275/p8651729

paula.williams@pennmedicine.upenn.edu

Role of human aldo-keto reductases (AKRs) in steroid hormone signaling and chemical carcinogenesis. In the former area we are elaborating the role of AKR1C3 in prostate cancer and polycystic ovarian syndrome. In the latter case we are elucidating the role of AKR1C enzymes in the metabolic activation of nitroarenes, which are constituents of diesel exhaust. We employ enzymology, analytical chemistry and cell and molecular biology techniques.

steroid enzymology; liquid chromatography/mass spectrometry; enzyme purification; mammalian cell culture

https://www.med.upenn.edu/apps/faculty/index.php/g275/p12620

While biofilms - complex polymeric structures that protect embedded microbial communities from stress - adversely affect the health of millions of human beings, diminish crop production, and are the cause of economically significant corrosion, they also play beneficial roles in several bioengineering applications such as bioremediation, biocatalysis, and wastewater treatment. In many prokaryotic species, the evolutionarily conserved type IV pili are required for surface adhesion and cell aggregation, but the regulatory mechanisms that control biofilm formation and dispersal are not well understood in most species. Recent studies in our lab indicate that, in the model archaeon, Haloferax volcanii, differential expression and N-glycosylation of a subset of type IV pilins, the constitutive subunits of type IV pili, play important and novel roles in regulating and facilitating the initial steps in biofilm formation. Moreover, genetic screens performed in our lab have identified components of the chemotaxis system as well as homologs of known circadian rhythm components and components involved in lipoprotein homeostasis as playing important roles in regulating biofilm dispersal. Using a strategy that combines approaches from biochemistry, genetics, and cell biology, with advance quantitative mass spectrometric methods, we will expand upon these results by analyzing the changes in glycoproteomic profiles that occur during the transitions from free swimming planktonic cell to biofilm-embedded cell at various stages of biofilm formation as well as during dispersal. Results from these studies will help to uncover the mechanisms through which differential pilin expression and N-glycosylation affect biofilm development and will also lead to the identification and characterization of additional proteins that play roles in controlling the transitions between planktonic and sessile cell.

biofilm, cell shape, lipoprotein homeostasis, cell surface biogenesis

https://www.bio.upenn.edu/people/mecky-pohlschr%25C3%25B6der

The overall goal of my research is to combine studies on fundamental mechanisms of skeletal cell function with translational medicine approaches to treat skeletal diseases. My group uses a combination of molecular, biochemical, imaging techniques, and animal models to investigate the molecular mechanisms by which hormones and growth factors regulate bone metabolism and skeletal development under normal and pathological conditions. In the past decade, I have made some groundbreaking discoveries that greatly advance our understanding of molecular regulation of bone metabolism, stem cell biology, and skeletal development and provided promising therapeutic tools for skeletal disorders. These achievements are well documented in senior and collaborative authored publications in the most influential journals in the bone field and acknowledged by my continuous grant support from Federal agencies (NIH R01, R21, R03, and Career Development Award) and private foundations.

stem cell, osteoporosis, osteoarthritis, facture healing, skeletal development

Our lab investigates circadian (24 hour) clocks and sleep. These two processes distinct, but highly related. We are particularly interested in the molecular mechanisms underlying clocks and sleep, and use a number of model systems (cells, organoids, Drosophila, mice) and technologies (RNA-seq, scRNA-seq, proteomics, metabolomics, live cell imaging, in vivo mouse imaging and behavior) to probe the workings of these systems. We are also interested in physiological and pathological relevance of clocks and sleep and have investigated gating of virus infections by the clock previously. We are extending this to look at SARS-CoV-2 (COVID-19) infection and its relationship to clocks, and possibly sleep.

Circadian clocks, sleep, genomics, virus, SARS-CoV-2

Our research group uses traditional and advanced tissue engineering approaches to address fundamental biologic questions related to the structure and function of normal and malignant epithelial tissues. The experimental platforms are flexible, and allow us to explore a broad scientific scope that encompasses cancers arising in skin or other organs, immune response to tumor, skin pigmentation, and epidermal differentiation. Projects are designed to advance foundational knowledge that informs rational design of new targeted therapeutics. We also devote significant effort to preclinical IND-enabling efficacy and toxicity studies to advance our discoveries toward human trials.

melanoma, sex differences in cancer, cancer immunology, genetic ancestral origin and cancer risk

Dr. Riley’s lab studies the signals that control primary human T cell activation and function with special attention to how these manipulations can be exploited to develop T cell therapies for HIV, autoimmune disease and cancer. We are studying how to best re-direct and expand human T regulatory cells for use in the treatment of autoimmune disease. We are evaluating both the use of TCR and CARs to redirect Tregs and studying both how these methods provide antigen suppression and if these approaches alter T regulatory cell stability. Part of this research is studies to understand how altering the media by which T cells are expanded in alters their function and engraftment potential in vivo. These studies have spurred interested on how various metabolic pathways are perturb by external signaling and environment. The lab is also focused on designing HIV resistant, HIV specific T cells to be key players in the HIV Cure effort. As a leader of the BEAT HIV Martin Delaney Collaboratory his lab is evaluating ways to make T cells resistant to HIV entry and integration and developing HIV-1 specific chimeric antigen receptors to evaluate the ability of these T cells to control HIV replication in both in vitro and humanized mouse studies. Dr. Riley’s basic research findings using primary human T cells have been used as the basis and rationale for numerous Phase I adoptive T cell therapy clinical trials.

T cell therapy; HIV; metabolism; transformation; autoimmunity

We are a human immunology research laboratory based at the Children's Hospital of Philadelphia. Our focus is on discovery of new inherited diseases of the immune system and human models of immunological tolerance. We conduct our investigations using primary human tissues (blood, tonsils, lymph nodes) and cell lines derived from human tissues. We use a variety of cellular and molecular techniques including CAS9 edited lines, RNA-seq, ATAC-seq and employ an array of functional immunologic assays.
Our lab is located on the 12th floor of the Abramson Research Center (ARC) at CHOP, which houses a vibrant community of immunology and microbiology investigators. There are currently 6 members of the lab (2 PhD post-docs, an MD fellow, a tech and a Penn undergraduate) and we welcome rotation students interested in translational immunology to join us.

primary immunodeficiency, B cell development, germinal center biology, T follicular regulatory cells.

In the Rompolas lab we use advanced microscopy and mouse genetic tools to study the cellular basis of tissue regeneration. Our goal is to understand the mechanisms that stem cells employ to maintain and replenish adult epithelia throughout life and to uncover which of these processes, when deregulated, are responsible for the emergence of disease. Taking advantage of the universality of basic biological mechanisms we will employ our learnings from the mouse model for the understanding and treatment of human disease.
External epithelia, such as the skin and cornea, protect and insulate our organs from the environment and in many ways make us who we are. On a daily basis billions of cells reach the end of their life cycle and are shed from our skin but they are soon replaced by new ones through the action of resident adult stem cells. Despite extensive research, a few fundamental questions remain regarding the skin regeneration process. How do the stem cells know precisely how many new cells to make and where to deliver them so that a perfect balance is maintained over time? How do the epithelial stem cells that regenerate the hair and the epidermis in the skin communicate with other cell types and the skin microenvironment? What causes the behavior of stem cells to change and how does this lead to a disease?
Using mouse genetic models and live imaging approaches we aim to: i) Uncover the genes that control stem cell identity and fate in tissue maintenance and regeneration, ii) Elucidate the mechanism of epithelial stem cell plasticity in response to injury and iii) Investigate how stem cells interact with elements of the tissue microenvironment in homeostasis and pathophysiology.

stem cells, tissue regeneration, skin, cornea, hair follicle, wound healing, live imaging

The focus of my research is the study of the blood coagulation protein factor VIII and the development of novel therapeutic approaches to treat hemophilia A. Hemophilia A is a bleeding disorder caused by mutations in the factor VIII gene. Current treatment for this disease is protein replacement therapy that requires frequent infusion of the factor VIII protein. The major complication of this treatment is the development of an immune response to the factor VIII protein that occurs in ~25% of hemophilia A patients. Our goal is to achieve sustained therapeutic levels of factor VIII expression so that patients no longer require frequent protein treatments. The continuous factor VIII expression would prevent bleeding episodes and may ensure that immune tolerance to the protein is established.
Studies in our laboratory have identified novel human FVIII variant proteins that have higher specific activity and increased secretion. We have introduced these variants into adeno-associated viral (AAV) vectors for hepatocyte targeted delivery of these proteins to improve factor VIII expression. AAV delivery of these FVIII variants in hemophilia A mice and a novel hemophilia A dog model that is tolerant to human FVIII supports the development of these variants in gene-based approaches. In addition, we study the potential immunogenicity of these novel FVIII proteins. In recent studies, we are developing strategies to target FVIII expression to liver sinusoidal endothelial cells, the natural site of FVIII synthesis, using AAV vectors. We are interested in understanding the biological differences between endothelial-derived and hepatocyte-derived FVIII including specific activity, cellular stress response and immunogenicity. Other studies in the laboratory focus on AAV integration and understanding the mechanisms involved in the integration of forms of AAV vector.

development, psychiatry, MRI, networks, machine learning

My research is directed towards understanding the development, regulation and maintenance of protective and pathologic CD4+ and CD8+ T cells in order to design new vaccines and immunotherapies for infectious diseases, focusing primarily on the protozoan parasite. The laboratory integrates results from studies in experimental murine models and those done in Leishmania braziliensis patients in Brazil, which allows the laboratory to develop hypotheses from human studies and test those hypotheses by doing mechanistic studies in mice. Currently, my laboratory focuses in three main areas: 1) defining the role of CD8+ T cells in mediating increased pathology and using that information to develop immunotherapies to accelerate healing in Leishmania braziliensis patients; 2) defining how CD4+ T resident memory cells develop and are maintained in order to target them in a vaccine; and 3) understanding the role of the skin microbiome in regulating the immune response to leishmaniasis. I have a long-standing collaboration with Drs. Edgar Carvalho and Lucas Carvalho at the University of Bahia, Salvador, Brazil. Our lab has mapped out the immunopathology associated with Leishmania braziliensis infections in patients in a series of publications, and based upon our findings we are currently designing host-directed therapies that would augment anti-parasitic drug treatment.

Immunology, Infection, Pathology, T cells, Parasites,

The laboratory seeks to understand the molecular and cellular networks that drive behavior, in particular rhythmic behaviors such as sleep. Our studies are done largely with the fruit fly, Drosophila melanogaster, but we also translate our findings to mammalian models, especially mice. The major goals are to elucidate the mechanisms that confer a circadian (~24-hour) periodicity on much of behavior and physiology as well as understand how and why the drive to sleep is generated.
Circadian (~24-hour) clocks endogenous to most organisms drive daily rhythms of sleep:wake and of most physiological processes. Any kind of desynchrony between endogenous clocks and the environment, as is caused by travel to a different time zone or by shift work, results in a multitude of physiological disturbances. Likewise, sleep disruption, which is common in modern society, results in severe metabolic and cognitive deficits.
Our research has provided insight into mechanisms of the circadian clock, how clocks synchronize to light and how clocks interact with body systems to drive rhythms of behavior and physiology. Building upon a Drosophila model for sleep that we developed several years ago, we have also identified genes and circuits that underlie the homeostatic drive for sleep. Ongoing studies are revealing new mechanisms and cellular functions for sleep. Together our studies are providing a comprehensive understanding of how internal clocks drive body rhythms, how and why a sleep state occurs, and the extent to which clocks and sleep impact general physiology and aging.

sleep, circadian rhythms, genetics, Drosophila, mouse, cell culture

Research focus: The central theme of Dr. Li Shen’s lab is focused on developing computational and informatics methods for integrative analysis of multimodal imaging data, high throughput omics data, cognitive and other biomarker data, electronic health record data, and rich biological knowledge and resources (e.g., pathways and networks), with applications to various complex disorders. The goal is twofold: (1) advance computer science and bioinformatics by producing novel algorithms for analyzing large scale heterogeneous data sets; and (2) provide important new insights into the phenotypic characteristics and genetic mechanisms of normal and/or disordered biological structures and functions to impact the development of new diagnostic, therapeutic and preventative approaches. Details about example research projects are available at https://www.med.upenn.edu/shenlab/research.html.

Potential topic #1: Develop bioinformatics and machine learning strategies for identifying brain imaging genetics associations manifest in the human brain transcriptome or epigenome, with application to the study of Alzheimer’s disease.
Potential topic #2: Develop bioinformatics and machine learning strategies for identifying imaging endophenotypes as mediators linking genetics to phenotypic outcomes, with application to the study of Alzheimer’s disease.
Potential topic #3: Develop bioinformatics and machine learning strategies for integrating brain imaging and genetics data for prediction of outcomes of interest such as disease stage, impairment score, and progression status.
Potential topic #4: Develop bioinformatics and machine learning strategies for identifying cell-type specific brain imaging genetics associations, with application to the study of Alzheimer’s disease.
Potential topic #5: Develop federated learning strategies for identifying brain imaging genetics associations from multiple cohorts, with application to the study of normal or disordered brain.

Medical image computing, bioinformatics, machine learning, big data science, imaging genomics, Alzheimer’s disease, brain science

Our research group investigates the genetic regulation of cell development and differentiation by studying genetic diseases of bone formation, mainly fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH). Both of these rare human disorders are characterized by heterotopic ossification: de novo formation of bone outside of the skeleton. In FOP, the ectopic bone forms in deep connective tissues such as muscle; and in POH, bone formation initiates within adipose tissue in the skin. Our group identified the mutated genes that cause these conditions, uncovering key regulators of cell fate decisions and tissue formation.
We continue to explore the cellular and molecular basis of the dysregulated stem cell fates, bone tissue formation, and the effects on skeletal development, using several complementary approaches and technologies, including molecular and cell biology, biomechanics, developmental biology, genetics/genomics, in vivo and in vitro models. We have developed mouse models that mimic both FOP and POH. Multiple lines of investigation are examining how the pathways that are perturbed in FOP and POH regulate stem and progenitor cell populations and the interacting cells in their tissue microenvironments to direct bone formation. Our goals are to understand how the cellular pathways that regulate bone development and formation induce ectopic bone formation, and to use this information to develop treatments for these and other disorders of bone.

Bone formation, cell differentiation, rare genetic disease, bone, cartilage, bone morphogenetic protein, BMP, ACVR1, fibrodysplasia ossificans progressiva, FOP, G-proteins, GNAS, progressive osseous heteroplasia, POH

https://www.med.upenn.edu/apps/faculty/index.php/g20000320/p9320

Investigating the mechanisms controlling blood vessel growth and sizes in development and disease using zebrafish

angiogenesis, zebrafish, blood vessel, arterio-venous malformation, artery formation, imaging

We study metabolic adaptations and stress responses in the tumor microenvironment that impact tumor growth, metastasis, and immune responses. We are particularly interested in the metabolic interplay between tumor cells, fibroblasts, and immune cells. To explore these questions we combine analysis of patient material with robust mouse models of kidney, liver, and pancreatic cancers, and well as soft tissue sarcomas.

tumor microenvironment, metabolism, tumor immunity, hypoxia and nutrient deprivation

The Song lab aims to understand the cellular and molecular basis governing the formation, maintenance and function of neural circuits under physiological and pathological conditions, combining fly and mammalian models.

regeneration, degeneration, Drosophila, optogenetics, metabolic reprograming

The microbial environment has a profound impact on the host immune system. However, how continuous “tickle” from the environment impacts host immunity remains poorly understood. We are interested in the fundamental question of how microbial experiences modulate T cell responses in humans. The lab combines patient-derived samples with high-dimensional approaches to generate a comprehensive understanding of T cell responses in the setting of infection, vaccination, and autoimmunity.

T cells, autoimmunity, vaccine, commensal microbes

We study the integration of environmental signals into human physiology. We are interested in understanding how individual lifestyle elements, such as nutrition, exercise, stress, temperature, and circadian rhythms, contribute to the pathogenesis of major human diseases, including neurodegeneration, cancer, cardiovascular disease, and inflammatory bowel disease.
Our strategy is to study the sensing systems of the human body (the nervous system, the immune system, and the microbiome) and their mutual interactions. Our goal is to understand how changes in environmental factors influences these systems and how this contributes to disease development.
To achieve this, we are using technologies from the fields of immunology, neuroscience, metabolism, microbiology and bioinformatics, and apply these techniques to both animal models of disease and human cohorts.

microbiome, gut-brain axis, neuro-immune interactions, immuno-metabolism, aging, metabolic disease, cancer, neurodegeneration

Thomas-Tikhonenko

Childhood cancers typically have low mutation burdens, and thus are much less likely to express neoantigens, and hence be susceptible to immune checkpoint blockade therapies. The apparent paucity of tumor-specific targets is likely to limit future immunotherapies – unless a new source of neo-epitopes (distinct from missense mutations) can be identified. We hypothesize that one such source could be alternative splicing. Specifically, we predict that non-canonical exon usage plays a dual role in acute lymphoblastic leukemia and potentially other cancers. On the one hand, it provides cancers with intrinsic mechanisms of epitope loss, which can render targeted immunotherapy ineffective. On the other hand, alternative splicing could be a source of cancer-specific epitopes and as such could aid immunotherapy. By simultaneously exploring the effects of alternative splicing on antigen loss and neo-epitope gain, we aspire to lay ground for the development of new immunotherapeutics that would target pediatric cancers with the specificity current modalities do not possess. Additionally, our newest preliminary data indicate that independently of acquired mutations, aberrant splicing of select transcripts contributes to chemoresistance and that correcting expression of relevant splicing factors could restore sensitivity to common anti-leukemia drugs.

cancer, pediatric leukemias, immunotherapy, chemotherapy, non-coding RNAs, RNA splicing

https://www.med.upenn.edu/apps/faculty/index.php/g20000320/p3080060

We are applying integrative evolutionary genomics approaches to address fundamental questions about human evolutionary history, local adaptation, and the genetic and environmental factors influencing both normal variable traits and disease susceptibility with a focus on African populations. We integrate field work in Africa with empirical and computational analyses. We are part of the NIH TOPMED consortium which aims to use integrative genomics approaches to identify genetic and epigenetic factors influencing cardiovascular health and disease. We are also part of the Human Cell Atlas Consortium which aims to characterize single cell gene expression to develop reference maps of all human cells.

human genetics, evolution, adaptation, genomics, epigenetics, gene expression, single cell, GWAS

Developing and applying smarter and more interpretable machine learning (ML) is critical to biomedical data mining and many other real world applications. The URBS-lab is focused on investigating ML methods that can select features and generate predictive/interpretable models, in the presence of complex associations. Tackling these challenges can improve our understanding of disease etiology, risk prediction, and personalized medicine. Specifics projects can be tailored to the interests and learning objectives of prospective students typically focusing on methods development or the application of ML methods to real world biomedical investigations based on current collaborations.

machine learning, informatics, artificial intelligence, data mining, complex systems, genetic heterogeneity

lung, develoment, regeneration, influenza, COVID-19

https://www.vet.upenn.edu/research/centers-laboratories/research-laboratory/vaughan-laboratory

A central aim of my lab is to understand the genetic determinants of cardiometabolic disease, including type 2 diabetes, heart disease, or non-alcoholic fatty liver disease. To build this understanding, the lab constructs and applies computational and statistical tools to genetic data collected across thousands of human genomes. Inferences made by our approaches are geared ultimately towards the identification of new targets by which novel therapeutics can be envisaged. We also develop methods to characterize rate of human mutation and evidence of natural selection in human populations, using population genetic studies. We have active engagement in the Million Veteran Program, a national study of Veterans who have been deeply genotyped for which phenotyping via electronic health records data is available. Many projects related to human genetic association studies, quantitative genetics, or causal inference studies using these data are also available. Rotation projects can be develop around data analysis or preliminary investigation of new methods applicable to these data or questions centralized around the use of human genetics data.

Human genetics, population genetics, computational biology, cardiometabolic disease, mendelian randomization, virtual screening

Understanding the flow of energy in cells and the disturbance of that flow during disease is critical for developing new therapeutic approaches to disease. That’s where the Center of Mitochondrial and Epigenomic Medicine (CMEM) at Children's Hospital comes in. Led by Douglas C. Wallace, Ph.D., CMEM is poised to advance the understanding of, and potential treatments for, a multitude of disorders and diseases by focusing on mitochondria, cellular structures that produce 90 percent of the body's energy.
The Center, established in 2010, takes the need to understand cellular energy a step further by investigating the communication between the mitochondria and nuclear DNA, and the crosstalk between them that is mediated by the epigenome.
With a mitochondria pioneer and internationally renown investigator at the helm, the Center is actively investigating mitochondrial and epigenomic dysfunction in a wide range of clinical problems that include autism, epilepsy, heart disease, diabetes and obesity, forms of blindness, Alzheimer and Parkinson disease, cancer, and aging.
In addition to examining the essential roles of mitochondria, the CMEM team explores how mitochondrial genes influence adaptation to environmental extremes such as arctic cold, tropical heat, or high altitude. The Center also focuses on preclinical studies relevant to developing therapies for mitochondrial dysfunction, for which few effective clinical treatments currently exist.

Mitochondrial Medicine, Epigenomics, Mitochondria, Genetics, Genomics, Pathology, Bioinformatics, Disease, Mitochondrial DNA, mtDNA, mitochondrial dysfunction, gene therapy, CMEM, aging, alzheimer's, alzheimers, neurological, autism, epilepsy, heart disease, diabetes, obesity, blindness, optic atrophy, parkinson's disease, parkinson, cancer, aging

Reprogramming of germline stem cells, epigenetics in reproduction, silencing of transposable elements, piRNA biogenesis, m6A RNA modification, regulation of meiosis, DNA recombination, chromosome segregation, DNA double-strand break repair, chromosome synapsis, male infertility in humans.

Development, stem cells, epigenetics, small non-coding RNAs

http://www.vet.upenn.edu/research/research-laboratories/research-laboratory/wang-laboratory

We seek to understand the neural and homeostatic mechanisms that control wakefulness and sleep in health and disease. We are particularly interested in REM sleep - the sleep stage associated with vivid dreaming - as this brain state constitutes a unique neurophysiological and neurochemical environment, which largely impacts the status of neural circuits and single neurons.
We study these questions in the mouse model employing an inter-disciplinary approach including optogenetics, in vivo electrophysiology, calcium imaging, viral tracing, behavioral assays, and computational modeling.

Sleep, Systems Neuroscience, Electrophysiology, Optogenetics, Calcium imaging, PTSD

The White Laboratory researches how human papillomaviruses cause cancer. We work at the interface of virology, cell biology, and immunology to investigate mechanisms by which HPV promote abnormal cell growth and evade immune detection. Our collaborators include basic scientists and clinicians. Two CAMB students are currently conducting their thesis research in our lab.

virus, virology, papillomavirus, HPV, cancer, inflammation, differentiation, cell biology

Most of the eukaryotic genome is transcribed, yielding a complex repertoire of RNAs that includes tens of thousands of noncoding RNAs with little or no predicted protein-coding capacity. Among these are well-studied small RNAs, such as microRNAs, as well as many other classes of small and long transcripts whose functions and mechanisms of biogenesis are less clear – but likely no less important, especially since some are associated with diseases such as cancer and developmental disorders. Our goal is to characterize the mechanisms by which these poorly characterized noncoding RNAs are generated, regulated, and function, thereby revealing novel insights into RNA biology and developing new methods to treat diseases.

RNA, gene expression, transcription, noncoding RNAs, translation, circular RNA, Integrator, splicing

Epigenetic mechanisms such as DNA modifications have profound impact on gene expression dynamics, stem cell differentiation, as well as organ maturation and aging (e.g. heart and brain). Our group seeks to investigate epigenetic gene regulation in these dynamic biological processes by developing high-precision (single-cell level or single-nucleotide resolution) and time-resolved genomics technologies. Our long-term goal is to use knowledge gained from quantitative and high-precision (epi)genomics analysis to identify biomarkers and to enhance stem cell therapy for treating human heart and neurodegenerative diseases.

Epigenetics, Gene regulation, Single-cell genomics, Neuroepigenetics

Our group develops and integrates computational and experimental methods, from deep learning to nanopore sequencing to single-cell technology, to study questions in transcriptomics, human genetics, precision medicine, and cancer immunotherapy.
We have a longstanding interest in understanding how RNA processing and regulation influence phenotypic variation and disease pathology. What can we learn from transcriptomes and proteomes about cellular and organismal phenotypes? How do perturbations in RNA regulatory networks contribute to disease etiology?
Our lab consists of people trained in a variety of different fields using both computational and experimental approaches to investigate these questions. We often tackle problems that cannot be directly solved using off-the-shelf methods. To this end, a major focus of our work involves developing state-of-the-art computational methods and genomic technologies that can yield new biological and clinical insights.
We welcome rotation students from either computational or experimental backgrounds. Potential topics for rotation projects include: (1) computational and experimental methods for transcriptome analysis using nanopore sequencing and microfluidics-based single-cell technologies; (2) genetic variation of transcriptome regulation and RNA processing in Mendelian and complex diseases; (3) clinical RNA-seq technologies for disease diagnosis or early detection; and (4) multi-omics and clinical data integration for precision oncology and cancer immunotherapy.

transcriptomics, human genetics, precision medicine, cancer immunotherapy, nanopore sequencing, single-cell technology

Our lab is interested in the biology of cancer and neurodegenerative diseases. Our current projects focus on two areas: (1) tumor suppression, metabolism, and autophagy, and (2) protein quality control (PQC) systems and neurodegenerative diseases.
Cancer encompasses over 100 diseases that occur in most cell types and organs of the human body. The relentless cell proliferation that characterizes malignancy is normally prevented by an intracellular tumor suppression network, with its central hub being the preeminent tumor suppressor p53. We are investigating functions and regulation of p53. Our recent results have revealed an important role for p53 in modulating metabolic pathways and autophagy that are crucial for cell proliferation. We are examining the function of p53 as both a sentinel and a regulator for various metabolic activities and autophagy. We are also studying common metabolic alterations that drive initiation and progression of various tumors. A recent extension of this research area is to define the role of metabolism and autophagy in stem cells, including embryonic stem cells and cancer stem cells, and to explore the utility of targeting these processes for cancer therapy.
Neurodegenerative diseases are becoming increasingly prevalent as the human population ages; yet they remain incurable. These diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), and polyglutamine diseases, are associated with misfolding and aggregation of proteins in the central nervous system, which ultimately leads to neuronal cell death. PQC systems are critically important in contending with protein misfolding and aggregation. Our lab recently identified two novel PQC systems in animal cells that are multifunctional and mechanistically distinct from canonical PQC systems. We are investigating the mechanism of action of these systems and their role in protecting against neurodegenerative diseases. We are also developing novel gene therapies based on these systems to treat neurodegenerative diseases.

Cancer biology, neurodegenerative diseases, embryonic stem cells, cancer stem cells, p53 tumor suppressor, metabolism, autophagy, protein quality control, signal transduction, gene therapy

https://www.med.upenn.edu/apps/faculty/index.php/g275/p20138

In order to survive and flourish in the world, animals ranging from vertebrates to invertebrates need to employ sophisticated feeding behaviors to effectively locate and discriminate foods. As such, a fundamental question arises as to how animals sense the complex food environment to control feeding behaviors. To tackle this question, we use model organisms such as the fruit fly to investigate how the chemical features of food, such as sweetness, bitterness and saltiness, and the physical properties of food such as food texture impact feeding behaviors. Specifically, using multiple approaches such as genetics, molecular and cellular biology, calcium imaging, and electrophysiology, we identity the receptors and the sensory cells that allow animals to detect the chemical and physical stimuli from the food environment. Moreover, we map the neural circuits in the brain that regulate taste sensation and food intake. Given that the peripheral and central neural mechanisms regulating food preference is highly conserved between insects and mammals, we propose that the molecular insights obtained from our studies in flies, will inform our understanding of the molecular and neural underpinnings of human feeding behaviors.

neuroscience, drosophila, sensory biology, ion channels, fruit flies, gustation, mechanosensation

1. DNA methylation-based computational decoding of differentiation and mitotic aging trajectory in human and mouse. Through this project, we hope to advance the understanding of the establishment of epigenetic cell identity and the progression of cellular aging using integrative modeling. We will investigate the quantitative contribution of epigenetic and genetic factors that jointly determine chromatin state evolution at different stages of organismal development.
2. Developing advanced informatics for Infinium DNA methylation BeadChip for mice. In collaboration with Illumina Inc and FOXO Biosciences, this project aims to comprehensively characterize this new assay platform that queries DNA methylation in mice. Students will develop a deep understanding of the Infinium BeadChip technology and co-author R/Bioconductor software while gaining experience in mouse genetics, epigenetics, and different mouse models for human disease.
3. Understanding tissue-specific mitotic turnover using long-read sequencing technology. The project leverages burgeoning long-read genomic profiling techniques to study different epigenetic factors that collectively govern stem cell turnover and cellular aging in single-cell resolution. In collaboration with bench scientists in the lab, we hope to resolve the long-standing puzzle of heterogeneity in the mitotic clock and its implication to cancer biology.
4. Informatics for cell type inference and rare cell type discovery using DNA methylation. We are developing an iterative learning framework and cell type assignment system by applying factor analysis to DNA methylome data. We will leverage the wealth of available single-cell and sorted tissue DNA methylome to reconstruct the spatial and temporal cell composition panorama for human tissue. The project aims to build out a comprehensive intelligent machine system that infers epigenetic cell identity through large-scale public data deconvolution and integration.

epigenetics, DNA methylation, bioinformatics, big data, machine learning, cellular aging, cancer

A fundamental question in Genetics and Neuroscience is how the brain executes genetic programs while maintaining the ability to adapt to the environment. The underlying molecular mechanisms are not well understood, but epigenetic regulation, mediated by DNA methylation and chromatin organization, provides an intricate platform bridging genetics and the environment, and allows for the integration of intrinsic and environmental signals into the genome and subsequent translation of the genome into stable yet adaptive functions in the brain. Impaired epigenetic regulation has been implicated in many neurodevelopmental and neuropsychiatric disorders. The Zhou laboratory is interested in understanding the pathophysiology of specific neurodevelopmental disorders with known genetic causes such as Rett syndrome and CDKL5 deficiency, and illuminating the pathogenesis of selective neuropsychiatric disorders with complex genetic traits such as autism and major depression. We use a variety of cutting-edge genomic technologies, together with cellular and physiological assays in genetically modified mice, to pursue our interests. The variety of research projects and experimental methodologies has allowed us to work with students from multiple graduate groups, such as G&E, NGG, GCB, BMB and PGG. Given the current COVID-19 pandemic, we have also started a new direction to combat SARS-CoV-2 to investigate the functional significance of protein glycosylation in the Spike protein and human ACE2. We aim to ultimately translate our findings into therapeutic development to improve the treatment for neurodevelopmental and neuropsychiatric disorders, as well as SARS-CoV-2.

Epigenetics, Neuroepigenetics, DNA methylation, Chromatin Organization, Genomic Editing, CRISPR, MeCP2, CDKL5, Neurexin, Rett Syndrome, Autism, Major Depression, SARS-CoV-2

https://www.med.upenn.edu/apps/faculty/index.php/p8330052