This is a summary list of all laboratories at University of Pennsylvania . The list includes links to more detailed information, which may also be found using the eagle-i search app.
Research in my laboratory focuses on the interrelationship between energy stores and regulation of energy balance by the brain. Contrary to the prevailing view of the adipocyte as merely a specialized cell for the storage of excess energy in the form of triglycerides, there is increasing evidence that adipose tissue plays a more active role in energy homeostasis. The levels of leptin, adiponectin, resistin and other hormones secreted by adipose tissue are dependent on the status of energy balance, and serve as important signals linking energy stores to peripheral and central homeostatic mechanisms. Adipokines also have profound effects on the neuroendocrine axis, and glucose and lipid metabolism.
Immuno-gene Therapy for Thoracic Malignancies
Lung cancer and other thoracic malignancies are the leading cause of cancer deaths in the United States today. The Thoracic Oncology Research Laboratory is focusing on the design of new treatment strategies for lung cancer and mesothelioma based on the rapidly evolving disciplines of molecular biology, immunotherapy, and gene therapy.
Dr. Albelda’s research is translational in focus and includes animal models, work with human tumor samples, and the conduct of clinical trials. This work is primarily funded through a recently renewed Program Project from the National Cancer Institute and participation in a number of RO1 grants.
The tumor microenvironment is one area of active study. Studies are underway with the goals of 1) a better understanding of the biology of the tumor microenvironment with a focus on the immunuosuppressive activities of white blood cells and fibroblasts, 2) novel approaches to alter the tumor microenvironment to enhance immunotherapy including studying effects using COX-2 inhibitors, TGFbeta inhibitors, T-regulatory cell inhibitors., antibodies against B-cells, and chemotherapeutic drugs. A second area of interest in the lab is the use of adoptive T cell transfer to treat lung malignancies. Studies are underway to modify T cells in order to make them traffic more efficiently into tumors, to have better killing function, and to resist inactivation by the tumor microenvironment. A T cells targeting cancer-associated fibroblasts is being developed. In addition, Dr. Albelda is closely involved with a number of immunogene clinical trials at Penn using an adenovirus expressing the immune-activator interferon-alpha that is instilled into the pleural space of mesothelioma patients (in collaboration with Dr. Daniel Sterman) and T cells altered to attack the mesothelioma tumor target, mesothelin (in collaboration with Drs. Carl June and Andrew Haas).
The Atchison laboratory is interested in determining the molecular mechanisms responsible for transcriptional regulation and the control of B cell development. To pursue these studies, we explore the functions of a number of transcription factors that regulate immunoglobulin gene expression and that play important roles in immunoglobulin locus structure, antibody maturation, lineage differentiation, and oncogenesis. We pursue our studies by biochemical, molecular biological, genetic, and developmental approaches using a variety of experimental systems including cell lines representing defined stages of B cell development, multipotential tumor lines, transgenic animals, and chimeric mice. General areas of current interest include:
1. Developmental control of immunogloblulin locus structure. Transcription factor YY1 is crucial for B cell development, and we found this factor can regulate immunoglobulin kappa V gene rearrangement and repertoire. Current data suggest that YY1 binds to numerous locations within the kappa locus and associates there with Polycomb Group, Condensin, and Cohesin proteins. We speculate that YY1 nucleates the binding of these factors to the kappa locus in a tissue-specific and developmental stage-specific fashion.
2. Mechanism of antibody maturation. Within germinal center cells antibody genes undergo somatic maturation processes involving class switch recombination and somatic hypermutation. Both of these processes require the enzyme, Activation Induced Deaminase (AID). Levels of AID in the nucleus are very tightly regulated and misregulation of AID leads to B cell lymphoma. We found that transcription factor YY1 can physically interact with AID leading to increased nuclear stability and increased class switch recombination. We are currently studying the mechanism of this stabilization, and the role of YY1-AID interaction in B cell lymphoma.
3. Function of the transcription factor YY1 as a Polycomb-Group protein in transcriptional repression and embryonic development. We found that human YY1 can function as a Polycomb protein in vivo to repress transcription and to control embryonic development. YY1 also recruits other PcG proteins to DNA resulting in specific histone post-translational modifications. We are studying the mechanism of this recruitment and specific proteins that bridge YY1 to the Polycomb Group complex repressor proteins.
4. Function of YY1 in B cell lymphomagenesis. Physical interaction of YY1 with AID may augment its role in germinal center derived B cell lymphomagenesis. We are using mice that spontaneously develop B cell lymphoma to determine the impact of YY1 overexpression and YY1 loss on lymphomagenesis and agressiveness.
5. Role of transcription factor PU.1 in hematopoietic development and enhancer chromatin structure. We found that PU.1 binds to immunoglobulin enhancers and recruits other proteins to DNA. Using PU.1 conditional knock-out mice and a variety of PU.1 mutants that ablate specific functions, we are exploring the role of PU.1 in enhancer chromatin structure, protein recruitment to DNA, and B cell development.
Our research focuses on developing mouse models of stress sensitivity related to neurodevelopmental and neuropsychiatric disease. We utilize genetic and prenatal manipulations to elucidate mechanisms contributing to disease predisposition.
We have focused on utilizing approaches that range from fetal antecedents in programming of long-term disease risk to genetic targeting of cell type specific knockout mice.
We have focused on developing models of disease including affective disorders and obesity utilizing approaches that range from fetal antecedents, involved in programming of long-term disease risk, to genetic targeting of cell type specific knockouts.
We have initiated multiple lines of investigation that will provide insight into the timing and sex specificity of early life events promoting disease susceptibility, the maturation of central pathways during key periods of development, and the epigenetic mechanisms involved in long-term effects following stress exposure.
The research in my laboratory focuses on the study of genomic imprinting and X inactivation in mice.
DNA double strand breaks (DSBs) are hazardous cellular lesions. Unfortunately, they also are very common. DSBs arise in every S phase through DNA replication errors and can be induced in any cell cycle phase by exogenous factors such as ionizing radiation or endogenous factors such as reactive oxygen species. When un-repaired or mis-repaired, DSBs can result in genomic instability that can lead to cell death or drive malignant transformation. Despite their danger, DSBs are a necessary part of biology. In this context, the induction and repair of DSBs within antigen receptor loci during V(D)J recombination and class switch recombination (CSR) is essential for development and function of an immune system capable of adapting and responding to a wide variety of pathogens. Cells have evolved efficient, specialized, and redundant mechanisms to sense, respond to, and repair DSBs. This generally conserved DNA damage response (DDR) integrates cell cycle progression and cellular survival to facilitate repair, or trigger apoptosis if damage is too severe. The physiological importance of V(D)J recombination and CSR control mechanisms has been demonstrated by the fact that defects in each can lead to immunodeficiency, autoimmunity, and lymphoma; while the immunological relevance of DDR control mechanisms has been illustrated by observations that deficiency of these can lead to immunodeficiency and lymphomas with antigen receptor locus translocations. One main research focus within the lab aims to elucidate molecular mechanisms through which the DDR maintains genomic stability and suppresses transformation in cells during V(D)J recombination, CSR, and DNA replication. Another research focus within the lab aims to exploit the knowledge and animal models gained through these studies to design, develop, and test novel treatments for cancer that are more effective and less toxic than current clinical therapies. A third research focus aims to elucidate the epigenetic mechanisms by which antigen receptor gene rearrangements are coordinated between homologous alleles and activated/silenced in a developmental stage-specific manner to maintain genomic stability and suppress cellular transformation during V(D)J recombination. Another research focus within the lab aims to test our hypothesis that the molecular mechanisms that control antigen receptor gene rearrangements and the cellular DDR co-evolved in lymphocytes to ensure development of an effective adaptive immune system without conferring substantial predisposition to autoimmunity or cancer upon the host organism.
The Behrens lab mainly focuses on dendritic cell biology and their function in normal and pathologic immune responses. In particular, we have developed an interest in Toll-like receptors (TLRs), a set of molecules on dendritic cells that recognize pathogens via common molecular motifs and initiate inflammatory responses. Within this theme of dendritic cell/TLR biology, the lab has two major arms of research:
1) TLR signal transduction ? TLRs have classically been thought to signal cells to generate inflammatory responses via two major signaling conduits, the MyD88 and TRIF pathways. However, there are many modifying and regulatory pathways that intersect with these tow major TLR signaling cascades. We are interested in probing the role of tyrosine phosphorylation events, mediated by Syk and the adapter protein Slp-76 in modulating TLR function in dendritic cells and macrophages.
2) Macrophage Activation Syndrome ? MAS is a rare, but fatal complication of a number of rheumatic, oncologic, infectious, and genetic disorders. In particular, 10% of patients with Systemic Juvenile Idiopathic Arthritis will develop fulminant, life-threatening MAS. The syndrome consists of a ?sepsis-like? clinical picture, and the pathologic hallmark of the disease is the hemophagocytic macrophage. These are macrophages, typically found in the bone marrow, that are phagocytosing other live hematopoetic cells such as red blood cells, platelets, or leukocytes. The pathoetiology of MAS in poorly understood, but is thought to be in part due to excessive CD8+ T-cell/antigen presenting cell (APC) interaction, resulting in overwhelming inflammation. While the T-cell determinants of this pathologic interaction have been reasonably well characterized, the APC side has not. Which APC plays a role in the disease, what APC inflammatory mediators, and what signal transduction pathways are critical to disease all remain unanswered and are potential areas of therapeutic development. Furthermore, the physiologic role of the hemophagocyte remains debated. We have developed a novel model of MAS in the mouse that does not depend on a genetic mutation but rather on repeated TLR stimulation, replicating the inflammatory environment seen in the rheumatic diseases associated with MAS. We have identified a complex network of cytokines, including IFNg and IL-10, and cell types that contribute to disease. We are currently working our the regulatory mechanisms behind these cytokines and cells to both provide insight into the fundamental immunology of MAS and develop novel therapeutics. We are also using transcriptome analysis to investigate the function of hemophagocytes to better understand their role in MAS.
The lab combines genomic and genetic data to computationally model RNA processing, followed by experimental verification to decipher post-transcriptional regulation, phenotypic diversity and disease
The ability to respond to nutritional stress is one of the most primitive adaptations that organism must accomplish. The pathways that alert the organism to an absence of food and initiate an appropriate response are remarkably well-conserved and involve such critical signaling molecules as the protein kinases Akt and AMP-activated protein kinase (AMPK) as well as nutrient sensors such as the carbohydrate response element binding protein (ChREBP).
The Birnbaum lab studies this complex biological response in two contexts: the initiation of cell growth after a transition from nutritional deprivation to abundance and the insulin-dependent redistribution of simple substrates into long-term energy stores. The latter process involves a number of distinct but interacting components such as glucose-stimulated insulin secretion, and the insulin-dependent acceleration of hepatic lipid synthesis and glucose uptake into adipocytes and muscle. Two aspects of the regulation of glucose transport by insulin, both of which are studied in the Birnbaum lab, are the way in which insulin regulates the movement of hormone-sensitive Glut4 glucose transporter from the inside of the cell to the plasma membrane, and the signaling pathway by which insulin accomplishes this. There are also a number of projects underway aimed at understanding how the evolutionarily conserved sensor of nutritional stress, AMP-activated protein kinase, regulates carbohydrate and fat metabolism. These fundamental biological problems are addressed using experiments performed in tissue culture cells, mice and the genetically tractable organism Drosophila melanogaster.
Research in our laboratory is heavily involved in the use of mass spectrometry for proteomics, lipidomics, and DNA analysis. We are particularly interested in determining the factors that control lipid hydroperoxide-mediated damage to DNA, RNA, and proteins. Methodology is being developed to characterize covalent modifications to these macromolecules using novel mass spectrometry techniques, determining how these can be evaluated as potential “biomarkers” of various physiological processes and disease states, and assessing how such processes can be prevented using novel pharmacological agents.
Our research focuses on the interplay of bacterial virulence mechanisms and host innate immune recognition strategies. We are interested in defining how bacterial pathogens are sensed by host cells, how this sensing contributes to antimicrobial immune defense, and how bacterial pathogens evade these innate immune recognition pathways.
The immune system utilizes two types of recognition strategies to detect microbes – membrane-bound pattern recognition receptors (PRRs), such as Toll-like Receptors, detect conserved microbial structures present in all microbes of a given class. Conversely, cytosolic receptors sense microbial virulence activities that result from the disruption of celluar processes or the inappropriate contamination of the host cell cytosol by microbial products. Notably, innate immune cells infected with a variety of unrelated bacterial pathogens, but not avirulent or non-pathogenic bacteria, undergo a pro-inflammatory form of cell death termed pyroptosis, which depends on the cellular protease caspase-1. Caspase-1 plays an important role in the cleavage and secretion of the pro-inflammatory cytokines IL-1ß and IL-18, and is therefore important in immune defense against various microbial infections. Members of the Nucleotide binding domain-Lecuine Rich Repeat (NLR) family of cytosolic signaling proteins recruit caspase-1 into multi-protein activating platforms termed ‘inflammasomes’. Inflammasome complexes are activated in response to a variety of bacterial, viral, and fungal infections and inflammasome activation plays an important role in host defense. However, successful pathogens have also evolved mechanisms to evade or subvert inflammasome activation, thereby avoiding caspase-1-dependent immune responses.
We use the Gram-negative bacterial pathogens Yersinia pseudotuberculosis and Salmonella typhimurium in combination with genetic, biochemical, and imunological approaches on both the bacterial and host side to understand the bacterial signals that trigger inflammasome activation, how inflammasome activation is coupled to innate and adaptive immune responses, and how bacterial pathogens evade inflammasome-dependent immune responses.
Recent studies in our laboratory have revealed unexpected links between caspase-1 activation and activation of other cell death pathways (Philip et al., PNAS 2014), and have identified a novel mechanism for sensing of TCA cycle metabolites by the NLRP3 inflammasome pathway (Wynosky-Dolfi et al., J Exp Med, 2014). Further studies have also demonstrated that bacterial pathogens tune the delivery of specific virulence factors into the host cell, so as to avoid triggering inflammasome response pathways (Zwack et al., MBio 2015)
Ongoing Projects in the Brodsky Lab involve (1) Dissecting the role of extrinsic cell death pathway components in inflammation. (2) Defining the contribution of inflammasome activation to anti-Salmonella immunity. (3) Determining the role of cell death in anti-bacterial immunity in vivo (4) Understanding the role of bacterial secretion system pore proteins in inflammasome activation
The focus of my lab is on the role of the cytoskeleton in T cell and dendritic cell function. The cytoskeleton is intimately involved in determining the efficiency and the fidelity of the immune response. For example, when a cytotoxic T cell recognizes a tumor cell for lysis, specific receptor interactions trigger capping of the cortical actin cytoskeleton, creating a specialized membrane domain that is important for T cell signaling events leading to lysis of the tumor cell. Similar processes are important for directing and modulating T cell help. In dendritic cells, actin regulatory proteins control the uptake and presentation of antigens, migration of antigen-bearing cells from sites of infection to lymphoid organs, and defining the outcome of T cell stimulation. Our long-term goals in the lab are to understand how receptor-ligand interactions at the cell surface trigger remodeling of the cytoskeleton, and how the cytoskeleton in turn affects the immune response. Proteins of current interest in the lab include WASP, an actin regulatory protein involved in immunodeficiency disease, HS1, a related protein implicated in autoimmune disease, and Crk family adapter proteins, proteins that control T cell adhesion and migration.
Research in the Bushman laboratory focuses on host-microbe interactions in health and disease, with particular focus on studies of 1) the human microbiome, 2) HIV pathogenesis, and 3) DNA integration in human gene therapy.
In recent years, our work has been driven increasingly by the remarkable new deep sequencing methods, which can produce more than 100 billion bases of DNA sequence information in a single instrument run.
For microbiome studies, this allows comprehensive analyze of microbial populations without reliance on culture-based methods, which can detect only a small fraction of all organisms present.
For studies of HIV replication, this allows analysis of complex viral populations or distributions of retroviral DNA integration sites in the human genome.
For gene therapy, this allows tracking of integrated vectors in gene-corrected subjects and molecular characterization of adverse events. Sample acquisition can sometimes be difficult in such projects, but bioinformatic analysis afterwards is almost always harder. We have been carrying out this type of study since 2002, when we showed that HIV DNA integration in human cells was favored in active transcription units, and over the years have built up partially automated software pipelines that allow efficient analysis deep sequencing data.
Lab members and collaborators cover a range of specialties, including clinical researchers, molecular biologists, computational biologists, and statisticians.
The goal of our work is to help make sense of the enormous amount of biomedical data generated by high-throughput genomic approaches and synthesize them into something more than the sum of the parts. To that end, we are developing tools that enable researchers to mine and integrate data from a variety of different sources and types of experiments. In particular we are applying these approaches to expand our understanding in the areas of diabetes and infectious disease. We model data with networks and reality with ontologies especially the Ontology for Biomedical Investigations (OBI) for the latter.
Our research goal is to develop, evaluate and apply novel computational methods and open-source software for identifying genetic and genomic biomarkers associated with human health and disease. Our focus is on methods that embrace, rather than ignore, the complexity of the genotype-to-phenotype mapping relationship due to phenomena such as epistasis and plastic reaction norms. Areas of interest include artificial intelligence, bioinformatics, biomedical informatics, complex systems, computational biology, genetic epidemiology, genomics, human genetics, machine learning, and visual analytics.
Our education goal is to provide interdisciplinary training and research experience to undergraduate, graduate, and postgraduate students. Our philosophy is that biomedical researchers of the future need to speak multiple languages to effectively collaborate with diverse teams of people focused on solving the hardest problems in health and healthcare.
The Curran laboratory studies brain development and pediatric brain tumors. The goal is to identify molecular changes and potential drug targets. Additional studies focus on the mechanism of action of anticancer drugs in tumor cells and cancer models.
Effector and memory lymphocytes, unlike naïve lymphocytes, can efficiently enter extralymphoid tissues as well as sites of inflammation and infection. Subsequently, lymphocytes enter the afferent lymph to reach draining lymph nodes. After a short time period of residency, lymphocytes exit the lymph node via the efferent lymph, which brings them back into the blood. This dynamic process of lymphocyte recirculation, which is tightly regulated at each step, is essential for immune surveillance and defense against pathogens, but it can also contribute to the development of inflammatory diseases.
My laboratory seeks to understand the regulation of lymphocyte recirculation as well as the microenvironmental localization of effector and memory lymphocytes within extralymphoid tissues, especially the skin. Currently, we are interested in defining the molecules involved in lymphocyte exit from extralymphoid tissues and the significance of this process to both protective and pathologic tissue immune responses. Another main interest of the lab is to determine the lymphocyte subsets involved in organ-specific immunity, with a focus on mobile surveillance mechanisms.
My lab uses a unique comparative immunology approach. We complement in vivo mouse models with a classic model of lymph cannulation in sheep that allows us to analyze lymphatic compartments that are inaccessible in rodents or humans. We also analyze human specimens to address whether our findings in ovine and mouse systems are relevant to human health. Finally, we are also committed to advancing general knowledge of the ruminant immune system, as domesticated ruminants are of worldwide importance.
Understanding the mechanisms involved in lymphocyte trafficking and recirculation through different organs not only reveals important components in the pathogenesis of inflammatory and infectious diseases, it also provides tools to therapeutically manipulate protective and pathogenic immune responses.
The Epstein Laboratory studies cardiovascular development, the genetics of congenital heart disease and cardiovascular regenerative and stem cell biology. The lab has a long-standing interest in congenital heart defects involving the outflow tract of the heart, the role of neural crest, the epicardium and the second heart field. More recent areas of focus include the cardiac inflow tract and the pulmonary veins and the origin of anomalous pulmonary venous return.
Other areas of interest include the factors and genes involved in progressive lineage restriction of cardiac progenitor cells and the role of epigenetics in progenitor cell expansion and differentiation. The lab is also interested in the implications of these studies for the development of new therapies for adult cardiovascular disorders including heart failure and arrhythmia. Specific projects have focused on the role of Notch and Wnt in cardiac progenitors, semaphorin signaling in the developing vasculature, the function of a novel homeobox gene Hopx and histone deacetylases in stem cells and the heart, and the role of the type I Neurofibromatosis gene (Nf1) in mouse and zebrafish cardiac development.
Our lab is part of the Department of Cancer Biology and the Abramson Family Cancer Research Institute, two outstanding collectives of scientists working on diverse cancer related problems. Our work is dedicated to deconstructing the multistep process of tumorigenesis with the ultimate goal of developing potent strategies to eliminate cancer.
Our laboratory has two areas of interest – prostanoid biology and the role of peripheral molecular clocks in cardiovascular biology, metabolism and aging. Perhaps the distinguishing feature of our groups is that we pursue interdisciplinary translational science with a focus on therapeutics. Thus, we work in different model systems – mammalian cells, worms, fish and mice – but also in humans. Ideally we develop quantitative approaches that can be projected from our experiments in the model systems to guide elucidation of drug action in humans. To this end, we have long utilized mass spectrometry, initially to target the arachidonate derived lipidome, but more latterly also the proteome.
Currently, we are interested in several aspects of prostanoid research. We utilize a remarkably broad array of mutant mice to elucidate the biology of the two COX enzymes and the prostanoid receptors. We are particularly interested in the comparative efficacy and safety of pharmacological inhibition of COXs versus the microsomal PGE synthase– 1. We are interested in the potentially countervailing actions of prostanoids on stem cell differentiation and in elucidating the broader cardiovascular biology of prostaglandins D2 and F2α. Finally, besides inhibitors of mPGES–1 we are interested in the translational therapeutics of various receptor antagonists, aspirin and fish oils.
In the area of clock biology, we are probing the role of the clock in aging in mice and worms and using cell specific deletions of core clock components to look at how communication paradigms between discrete peripheral clocks influence cardiovascular biology and metabolism. Finally, we are taking systems approaches to investigate how perturbation of peripheral clocks result in central clock dependent phenotypes.
Finally, we are involved in the interdisciplinary PENTACON consortium designed to integrate basic and clinical research in 5 systems – yeast, mammalian cells, fish, mice and humans ( both in detail and at scale) – with the objective of predicting NSAID efficacy and cardiovascular hazard in patients.
The Penn Physical Medicine and Rehabilitation Gait and Biomechanics Laboratory focuses on motion and gait analysis for both patient care and research in order to better diagnose, treat, and understand movement and gait disorders.
Gait analysis is covered by insurance to aid in surgical planning in patients with gait disorders associated with cerebral palsy. Gait analysis can still be used for other applications but will be charged as fee for service
We are studying a mutant gene which when homozygous leads to a lethal kidney disease in mice. These mice undergo a spontaneous autoimmune reaction which involves multiple immune pathways. We have cloned the relevant gene, and have found that it codes for a mitochondrial protein similar to trans-prenyltransferase. This enzyme is needed for isoprenylation of coenzyme Q (CoQ), and is now known as prenyl diphosphate synthase subunit 2 (Pdss2). The mutant mice have defective mitochondria, as demonstrated by ultrastructural analysis, and we believe that this defect leads to the death of glomerular podocytes. This in turn leads to an autoimmune response which involves both the tubular interstitium and the glomeruli. The kidney disease can be prevented to some extent by CoQ supplementation, and to an even greater extent by probucol. The mechanism by which probucol does this has not been fully elucidated, but we and our collaborators (Dr. Marni Falk at CHOP and Dr. Cathy Clarke at UCLA) have demonstrated that it increases the endogenous production of CoQ.
In collaboration with Dr. Julie Blendy, Dr. Harry Ischiropoulos, and their students, we have demonstrated that these mutant mice also have neuromuscular defects that resemble Parkinson’s disease. We are currently working on several possible therapies which have the potential of treating these problems.
The human disease with the greatest similarity to this phenotype is focal segmental glomerular sclerosis, or FSGS. It is well known that there is a significant genetic component to FSGS susceptibility, and in collaboration with a group at the NIH, we have obtained evidence that PDSS2 is one of the genes that is involved in this susceptibility.
Our laboratory studies the mammalian circadian clock using genomic and computational tools. We use these tools to discover new clock genes, learn how the clock keeps time, and how it coordinates rhythms in physiology and behavior. This clock research drives development of genomic and computational methods that we apply to other areas of biology. Finally, we recognize biological complexity and conduct this research at the network, rather than single gene, level.
Dr. Hunter has been working on various aspects of basic parasitology since 1984 and for the last 25 years there has been a focus on understanding how the protective immune response to Toxoplasma gondii develops and how this relates to other parasitic infections.
The Hunter Laboratory team has focused on the innate events that lead to the development of long term protective immunity mediated by T and B cells. These studies led us to develop expertise in cytokine biology and, while the focus has been in understanding their role in infectious disease, these findings are frequently relevant to cytokine function in autoimmunity and inflammatory processes associated with human disease.
For example, as part of studies to understand how IL-12 family members affect immunity to the T. gondii, we showed that IL-27 was important in limiting the T cell-mediated infection-induced inflammation. We have defined the mechanisms used by IL-27 to influence the immune system and our work has been shown to be relevant to inflammatory processes in multiple experimental systems that includes other infections as well as models of auto-immune inflammation, asthma and cancer.
Since toxoplasma causes a chronic infection in the brain there has been a long-term interest in the neuropathogenesis of infectious diseases and how lymphocytes access and operate in this immune privileged site.
In this laboratory we have developed all of the skills required for the routine analysis of multiple innate immune parameters and to quantify DC, macrophage, NK, T and B cell responses to infection.
We are also able to utilize different combinations of transgenic parasites (replication deficient, expressing fluorescent reporters, distinct model antigens OVA and E and the Cre recombinase) and TCR transgenic T cells to provide higher resolution analysis of individual parasite specific CD4 and CD8 T cell populations and apply multi-photon microscopy to image the innate and adaptive response to T. gondii.
Asthma is a chronic inflammatory disease, which is associated with the recruitment of mast cells to the lung and their activation. It is well known that aggregation of high affinity IgE receptors (FceRI) on mast cells and the subsequent mediator release contributes to the development of allergic asthma. However, emerging evidence suggests that transactivation of G protein coupled receptors (GPCRs) for the complement component C3a contributes to the exacerbation of allergic diseases. The main focus of our laboratory has been to delineate how G protein coupled receptor kinases (GRKs) and the adaptor molecule β-arrestin regulate C3a receptor function in mast cells. We unexpectedly found that GRK2 and β-arrestin2 serve as novel adaptor proteins to promote IgE-mediated mast cell chemotaxis, degranulation and cytokine gene expression. We are currently utilizing both in vitro and in vivo approaches to delineate how GRK2 and β-arrestin2 regulate FceRI signaling in mast cells to modulate allergic asthma.
Surface epithelial cells, when activated by pathogen-associated molecular patterns (PAMPs) release small cationic antibacterial peptides (AMPs), known as defensins and cathelicidins. These AMPs display potent antimicrobial activity, modulate immune responses and likely participate in the exacerbation of allergic diseases such as asthma and urticaria. Recently, we made the unexpected observation that AMPs activate human mast cells via a novel GPCR (Mas-related gene X2; MrgX2). Most interestingly, we found that unlike C3a receptor, MrgX2 is resistant to regulation by GRK2 or β-arrestin-2. It is noteworthy that unlike human mast cells, murine mast cells do not express MrgX2 and are resistant to activation by AMPs. We are currently engrafting human CD34+ hematopoietic stem cells (HSCs) into severely immune-deficient mice. In addition to human immune system, these “HUMANIZED MICE” develop human tissue mast cells are responsive to AMPs for activation in vivo. We are currently using the humanized mouse model to determine the role of MrgX2 and its signaling on anaphylaxis and asthma in vivo.
Description of Research
Barrett’s Esophagus Focus:
Esophageal adenocarcinoma (EAC) has been the fastest rising malignancy in the U.S.. Several conditions increase the risk for the development of EAC, including obesity, smoking, diet, acid reflux, and, most significantly, Barrett's esophagus (BE). BE occurs at the gastroesophageal (GE) junction and is the replacement of normal squamous esophageal mucosa with an intestinalized columnar epithelium. It typically arises in response to chronic acid exposure and is associated with acid reflux. Importantly, the histologic precursor lesions and molecular mechanisms underpinning BE pathogenesis remain poorly understood. One reason is the paucity of experimental models for BE. Our research has focused on this problem, and the development of innovative, genetically based and physiologically relevant human cell culture and transgenic mouse models for BE is an important objective of my lab. We are broadly pursuing several strategies including exploring the role of intestine-specific transcription factors like Cdx1, Cdx2, and Hath1, as well contributions by proinflammatory cytokines (IL-1beta), eicosanoids (Cox-2), and autophagy in BE pathogenesis and progression to neoplasia.
Intestinal Stem Cell Focus:
Stem cells are defined by the capacity for long-term self-renewal and multilineage differentiation. Until relatively recently, our understanding of stem cell biology, as well as their role in many human disease processes from aging to cancer, has been rather limited. Moreover, interest in harnessing the stem cell’s capacity for self-renewal to promote organ and tissue regeneration cuts across many medical disciplines. Recently, genetic studies have identified several robust markers for stem cell populations in the intestine. These advances now make it possible to isolate stem cell populations for more advanced molecular investigations. One important challenge encountered by stem cells is to correctly determine their tissue identity based on environmental cues. Errors in stem cell identity are encountered in intestinal metaplasia of the esophagus and stomach, as well as many gastrointestinal cancers. We are exploring these questions using novel transgenic mouse models of gastric intestinal metaplasia and in mice with alterations in the intestinal stem cell niche.
More recently we have begin using live cell confocal microscopy to investigate how the intestinal stem cell niche is established, the relationship between niche and stem cells, how intestinal crypts fission, how stem cells undergo mitosis, and early events in neoplastic transformation.
T cells integrate multiple signals from their environment. The culmination of these signals direct the fate of developing thymocytes, dictating the outcome of thymocyte selection and T-regulatory (Treg) cell development. Mature peripheral T cells also integrate multiple signaling pathways during encounter with pathogens and are directed to differentiate into one of several T cell effector subsets.
We are interested in understanding how specific pathways direct these differentiation steps in thymocytes and peripheral T cells. Currently we are focusing on signaling pathways and epigenetic modifiers that have recently been implicated in T cell lymphomagenesis with an aim towards understanding how these pathways and enzymes direct both normal and malignant T cell biology. Some active areas of investigation include the following:
• T cell activation leads to transient changes in the activation states of many proteins and enzymes, but it also results in heritable changes at the epigenetic level. DNA methylation is a common epigenetic modification that is regulated via both active and passive mechanisms. TET2 is a methylcytosine dioxgenase involved in the active demethylation of DNA and is frequently mutated in a specific class of T cell lymphomas. Our lab has shown that TET2 regulates the development of memory CD8+ T cells as well as CD4+ T cell differentiation. We are currently identifying the targets of TET2 to understand the mechanism by which it regulates T cell differentiation. We are also interested in CXXC5, a negative regulator of TET2, to determine its TET2 –dependent and –independent functions in T cell activation and differentiation.
• The GTPase RhoA is important for thymocyte development and is activated downstream of the T cell receptor and integrins. RhoA regulates actin reorganization and has been implicated in T cell metabolism. Recently, RhoA mutations have been identified in T cell lymphomas, often co-occurring with TET2 loss-of-function mutations. Using both in vitro and in vivo models of regulated RhoA expression, we are investigating the mechanism of RhoA function in healthy and diseased states.
The Kaestner lab is employing modern mouse genetic approaches, such as gene targeting, tissue-specific and inducible gene ablation, to understand the molecular mechanisms of organogenesis and physiology of the liver, pancreas and gastrointestinal tract.
1) Regulation of T cell responses
T cells are pivotal players in the immune response. They are beneficial in combating infections and cancer but can also be harmful in autoimmunity and immunopathologic states. T cell activation is primarily initiated by intracellular signals emanating through their T cell receptor. These signals can be further modified by engagement of other cell surface receptors and by negative regulators of signaling. Currently, we study the role of the NK cell receptor NKG2D in controlling T cell activation. In addition, we are investigating the roles of negative regulators of calcium and daicylglycerol signaling in T cell activation and differentiation.
2) Regulatory T cell expansion and homeostasis
In addition to the cell-intrinsic regulation of T cell activation as described above, T cells are controlled cell extrinsically by regulatory T cells. Regulatory T cells represent a subset of CD4+ T cells that possess the ability to suppress the activation and expansion of other conventional CD4+ T cells. They are distinguished from conventional T cells by constitutive expression of CD25 and the transcription factor Foxp3. The importance of regulatory T cells is evidenced by the severe autoimmunity that develops in mice and humans lacking regulatory T cells. We are actively investigating how signal transduction processes affect the development, homeostasis, expansion, and function of regulatory T cells. We translate our findings to therapeutic approaches in the prevention of inflammatory diseases such as multiple sclerosis, graft-versus-host disease, diabetes, rheumatoid arthritis, and inflammatory bowel disease.
4) NK cell education and signaling
NK cells are innate immune cells that provide a critical line of defense against intracellular pathogens and tumors by displaying cytotoxicity and producing immune-activating cytokines. One key mechanism that regulates their activation involves the expression of activating receptors that are finely counterbalanced by inhibitory MHC class I-binding receptors. Thus, the interaction of NK cells with abnormal cells that have decreased MHC class I expression relieves the inhibition conferred by the MHC-binding inhibitory receptors, leading to activation and cytotoxicity by the NK cell. NK cells heterogeneously express one or more of the many inhibitory receptors, which are acquired by NK cells during later stages of their development. The heterogeneity of NK cell receptor expression allows NK cells to discriminate between cells expressing normal and abnormal amounts of various MHC class I molecules. As the signaling requirements of these receptors during development and effector function remain unclear, we have been investigating the signal transduction pathways during NK cell activation. In doing so, we have identified some key signaling molecules that are necessary for proper acquisition of MHC-binding inhibitory receptors during development. We are further investigating the molecular mechanisms that are responsible for regulating inhibitory receptor acquisition during NK cell development and how it relates to the functional outcome of the NK cell response.
A key property of living objects is that each object, whether they are proteins, cells, or whole organisms, has an associated generating process, that is, a decoding process whereby stored information is converted into a complex functioning biological object. For example, generating a protein involves translation and folding; generating an organism involves a cascade of gene regulatory and cell biological processes. We are interested in such bio-generative processes and understanding the temporal control and architectural constraints of these processes.
Questions include how to infer the organizational structure of such generative processes from available data, the evolution of control processes, and how the relationship between generative dynamics, variability, and the final form interact to determine the evolution of the biological object. Two central projects in our lab are using comparative transcriptome profiling of time-series to uncover the architecture of temporal control in yeast and using computational analysis of non-coding RNAs to understand the evolution of sub-cellular processes in neurons.
Since 2007, Jim Eberwine (Pharm) and I have been engaged in multiple joint projects concerning genomics of cell differentiation and cell diversity. Our labs collaborate in all kinds of projects where we bounce ideas off each other, design and carryout experiments together, and design analysis of data together. Many of the projects described below, especially in neuroscience are joint projects between our two labs.
In addition to these theoretical problems, we work on a wide range of collaborative projects and computational biology projects. Currently, these collaborations involve molecular control of neurons, functional prediction of sequence elements for genes involved in synaptic transmission, novel technologies for functional genomics, statistical analysis of whole-genome expression profiling, as well as software engineering bioinformatics analysis platforms. We employ a variety of techniques including discrete algorithms,simulations, statistical learning, dynamical systems and algebraic geometry, molecular biology, functional genomics, and single-cell genomics.
Our laboratory makes use of cell-free biochemical systems, model cell lines, and whole animals which have been genetically manipulated to probe various signal transduction pathways. Over the past several years we have become particularly interested in the regulation and integration of second messenger cascades by adapter molecules, those proteins which possess no intrinsic enzymatic properties, but which function by bridging protein-protein interactions.
Our laboratory is currently pursuing studies focused on mechanisms of B cell homeostasis and how these impact autoimmunity and aging. These have led to the characterization of a novel receptor for BLyS, a TNF family member that controls B cell numbers and determines the stringency of B cell selection.
Major histocomatibility complex (MHC) class II molecules are required for the normal development in the thymus of CD4+ T cells and function to present peptide antigens to those CD4 cells in the periphery.
The distribution of class II molecules is limited to thymic epithelial cells-where they are required for the positive and negative selection of CD4+ T cells-and in the periphery where they are required for the survival and activation of those T cells. We have developed a series of transgenic mice with restricted expression of the MHC class II molecule, I-Ab, and used them to investigate the requirement for different populations of antigen presenting cells in the thymic selection, peripheral activation, and tolerance of CD4+ T cells. Our most well studied model is the K14 mouse in which MHC molecules are restricted to thymic cortical epithelium-both thymic medullary epithelium and bone marrow-derived cells are class II negative. Positive selection of CD4+ T cells does occur in the K14 thymus; however, clonal deletion of autoreactive thymocytes can not be detected. Thus, K14 CD4 cells proliferate to I-Ab-positive APC in vitro and cause graft-versus-host disease when injected into MHC-identical hosts. Our current studies are directed toward understanding the peptide specificity, function, and pathologic potential of these autoreactive T cells:
1) Examination of a series of K14-derived autoreactive T hybridomas demonstrates that the autoreactive population of CD4 cells is polyclonal; however, we are beginning to identify the individual peptides responsible for stimulating the autoreactive response. To better understand the thymic selection processes in both K14 and wildtype thymi, we have also derived TCR transgenics from two of the hybrids and have begun to analyze the thymic development and peripheral function of autoreactive TCR transgenic CD4+ T cells in both K14 and wildtype mice of various haplotypes, including NOD, the diabetogenic genotype.
2) Development of autoimmunity: Adoptive transfer systems are being utilized to tease apart the T cell and target-organ abnormalities that must be present to initiate an autoimmune disease. Disease models include graft-versus-host disease, Herpes simplex keratitis, and Type I diabetes.
3) Requirement for MHC class II in other antigen presenting populations. Our newest transgenics utilize the mb-1 and CD11c promoters to reexpress class II molecules in the B cells and dendritic cells, respectively, of class II-deficient mice. Studies will be directed towards understanding how limiting the expression of Class II molecules alters the positive and negative selection, peripheral survival, and peripheral survival and effector function of CD4+ T cells.
Dr. Levine’s basic science research is focused on defining the role that histone deactylases (HDACs) and heat shock proteins (hsps) play in tolerance of renal ischemia-reperfusion, work that is now funded by the NIH. This work has demonstrated significant renal function protection via HDAC inhibition by drug and by gene knockout which has also been associated with substantial diminution of fibrosis after injury. Further work is investigating which specific HDAC pathways are involved and determining if the site of action is on the kidney or the inflammatory cascade. Additional directions of this work are defining the role that hsps play in renal ischemic damage and whether the expression of hsps is beneficial or detrimental to renal ischemic recovery. Additional work is investigating the role of gender and hormone milieu on the response to renal ischemic injury. Dr. Levine has additional collaborative basic science studies investigating the role of costimulation blockade and cytokine pathway manipulation in rejection or tolerance of limb transplantation in murine models, work that is being initiated with funding from the Department of Defense and is initiated in collaboration with Dr Wayne Hancock and Dr Scott Levin. Additional collaborative work with the Hancock laboratory involves the effects of typical immunosuppression strategies on human regulatory T cells (Treg) after transplantation.
We study the intricate interactions between respiratory viruses, such as parainfluenza and respiratory synctial virus, and the lung innate immune system. We seek to identify viral and cellular factors that drive the development of effective antiviral responses able to control virus replication and dissemination. Our long-term goals are to identify potent viral molecular motifs that trigger the host immune response and to harnness them as adjuvants for vaccination. We are also interested in discovering new determinants of virus pathogenesis that could be targeted to minimize acute and chronic post-viral disease.
Eukaryotic cells are compartmentalized into distinct membrane-bound organelles and vesicular structures, each with its own characteristic function and set of protein constituents. Work in my laboratory is focused on understanding how integral membrane protein complexes are assembled and sorted to the appropriate compartments within the late secretory and endocytic pathways, how sorting and assembly contribute to the biogenesis of specific organelles in several cell types, how these processes impact biological function in the pigmentary, blood clotting, and immune systems, and how they are thwarted by generally rare genetic diseases.
Our primary focus over the past 18 years has been on melanosomes of pigmented cells. Melanosomes are unique lysosome-related organelles present only in cells that make melanin, the major synthesized pigment in mammals. Genetic defects in melanosome constituents or in their delivery to nascent melanosomes result in ocular or oculocutaneous albinism, characterized by lack of pigmentation in the eyes and or skin and concomitant visual impairment and susceptibility to skin and ocular cancers. Melanosomes are among a number of tissue-specific lysosome-related organelles that are malformed and dysfunctional in a group of rare heritable disorders, including Hermansky-Pudlak and Chediak-Higashi syndromes, and pigment cell-specific proteins that localize to melanosomes are targets for the immune system in patients with melanoma. In an effort to understand the molecular basis of these diseases, we are dissecting the molecular mechanisms that regulate how different stage melanosomes are formed and integrated with the endosomal pathway. We use biochemical, morphological, and genetic approaches to follow the fates of melanosome-specific and ubiquitous endosomal and lysosomal proteins within pigment cells from normal individuals or mice and disease models. Using these approaches, we are (1) outlining protein transport pathways that lead to the formation of these unusual organelles, (2) dissecting biochemical pathways that lead to their morphogenesis, and (3) defining how these processes are subverted by genetic disease. Current efforts focus on how factors that are deficient in patients and mouse models of the genetic disease, Hermansky-Pudlak syndrome, impact melanosome biogenesis. We are particularly interested in how these factors contribute to the formation and dynamics of tubular connections between endosomes and maturing melanosomes that facilitate cargo transport, as well as the formation of retrograde membrane carriers that retrieve unneeded proteins from melanosomes.
Because genetic diseases like Hermansky-Pudlak syndrome affect multiple organ systems, we study how similar sorting processes involved in melanosome biogenesis influence other organelles in different cell types. The first involves lysosome-related organelles in platelets called dense granules and alpha granules. When platelets are activated at sites of blood vessel damage, the contents of these granules are released, leading to optimal blood clot formation and platelet activation. Like melanosomes, dense granules are malformed in Hermansky-Pudlak syndrome, and in collaboration with the Poncz, Stalker and French laboratories at CHOP and Penn we are studying how dense granule contents are delivered within platelets and their precursors (megakaryocytes). Studies in collaboration with the Poncz and French labs also address the contents and secretion of alpha granules and their disruption in human bleeding disorders.
The second cellular system is the dendritic cell, a master regulator of T cell-mediated immunity. Patients with Hermansky-Pudlak syndrome type 2 have recurrent bacterial infections, and we have found that this is at least in part due to defects in the way that dendritic cells sense bacterial infection. Normally, ingested bacteria trigger signaling by innate immune receptors present on the membrane enclosing the bacteria (the phagosome); this signaling is defective in dendritic cells from a mouse model of the disease due to impaired recruitment of the receptors and their signaling platforms. Ongoing studies aim to dissect how phagosome membrane dynamics normally lead to signaling and how this is altered in disease states.
Finally, melanosome precursors in pigment cells harbor intrernal fibrils upon which melanins deposit in later stages. The main component of these fibrils is a pigment cell-specific protein, PMEL. Fibrils formed by PMEL in vitro display features common with amyloid formed in disease states such as Alzheimer and Parkinson diseases. By dissecting how PMEL forms amyloid under physiological conditions, we hope to determine how the formation of "good" and "bad" amyloid differs and thus how the formation of "bad" amyloid might be controlled.
MIPG is one of the oldest and longest active research groups in the world engaged in research on the processing, visualization, and analysis of medical images and the medical and clinical applications of these computerized methods. It was formed in the Department of Computer Science, (then) State University of New York, Buffalo, in 1976 by Gabor Herman. Udupa joined the group in 1978. The whole group moved to University of Pennsylvania, its current home, in 1981. Udupa was appointed its director in 1991.
Our lab focuses on the developmental pathways and factors that are critical for building the cardiopulmonary system. Using a combination of mouse genetics, biochemistry, and genomic analysis, we seek to better understand how the lung and heart develop, how developmental pathways are disrupted in human cardiopulmonary disease, and whether such pathways and factors can be harnessed to promote pulmonary and cardiac regeneration in the adult.
Pemphigus vulgaris (PV) is a potentially fatal disorder in which autoantibodies against desmosomal cell adhesion molecules known as desmogleins cause blistering of the skin and mucous membranes. Our laboratory is interested in better understanding pathogenic mechanisms in this model organ-specific autoimmune disease, from both the immunologic and cell biologic perspectives.
A fundamental question in organ-specific autoimmune disease is why the immune system breaks tolerance against only a limited number of self-antigens. We have cloned B cell repertoires from PV patients to understand how they developed desmoglein autoreactivity. We have identified shared VH1-46 gene usage in anti-desmoglein 3 B cells from different PV patients and defined acidic amino acid residues that are necessary and sufficient to confer desmoglein 3 autoreactivity. These VH1-46 B cells are autoreactive to the disease antigen in the absence of somatic mutation or require very few mutations to develop autoreactivity, which may favor their selection early in the immune response. Common VH gene usage is significant, because it may indicate common mechanisms for developing autoimmunity in PV. Ultimately, shared structural elements of the PV B cell repertoire (e.g., VH or CH gene usage) may lead to safer targeted therapies for pemphigus. Ongoing projects aim to identify potential foreign antigenic triggers of the desmoglein autoimmune response in pemphigus, to identify the B cell subsets that produce the pathogenic autoantibodies, and to develop effective targeted therapies.
Our laboratory is also investigating the cell regulatory pathways that promote desmosomal adhesion. We have shown that the p38 MAPK/MK2 axis is a critical regulator of desmosomal adhesion in keratinocytes and that inhibition of this pathway can ameliorate pemphigus skin blistering. Ongoing projects are studying the regulation of desmosomal adhesion and desmosomal protein expression in keratinocytes to better understand how anti-desmoglein antibodies cause the loss of cell adhesion and how we might interfere with these pathways to improve disease.
The Rader laboratory is focused on two major themes: 1) novel pathways regulating lipid and lipoprotein metabolism and atherosclerosis inspired by unbiased studies of human genetics; 2) factors regulating the structure and function of high density lipoproteins and the process of reverse cholesterol transport and their relationship to atherosclerosis. A variety of basic cell and molecular laboratory techniques, mouse models, and translational research approaches are used in addressing these questions.
The use of both genetic and molecular approaches to the study of virus-host interactions in vivo provides us with insight into the processes that determine the susceptibility and resistance of individuals to viral infection and virus-induced cancer (approximately 20% of human cancers). Our interests lie in determining why viruses infect specific hosts and how in turn, host genes confer resistance to this infection. Our lab studies 2 different types of viruses, retroviruses like mouse mammary tumor virus (MMTV) and murine leukemia virus (MLV) which cause cancer in mice, and the new world arenaviruses, which cause hemorrhagic fever in humans.
The genetics of susceptibility is easily studied with naturally-occurring pathogens in inbred and genetically-manipulated mice. MMTV is an endemic oncogenic retrovirus that has been an infectious agent in mice for > 20 million years, while MLV has been in mice ~ 3 million years. Infectious MMTV is passed from mothers to offspring through milk and first spreads in lymphoid cells before infecting mammary epithelial cells; MLV is probably also milk-transmitted. These viruses thus serve as models for the human milk-borne retroviruses HIV-1 and HTLV1. MMTV causes breast cancer and MLV causes lymphomas when the viral genome inserts next to cellular oncogenes by activating their expression. Our studies focus on understanding the mechanisms that determine susceptibility to MMTV infection and virus-induced mammary tumors and we have identified a number of genes and mechanisms that confer resistance to infection by MMTV and MLV.
Genes of the immune system play a major role in susceptibility to infection, and one gene which we recently discovered is involved in the control of MMTV and MLV infection is Apobec3. All mammals encode Apobec3 genes which play a role in intrinsic cellular immunity to a number of viruses, including human immunodeficiency virus type 1. APOBEC3 proteins are packaged into virions and inhibit retroviral replication in newly infected cells, at least in part by deaminating cytosine on the negative strand DNA intermediates. We found that mouse APOBEC3 protein is packaged into MMTV and MLV particles in vitro and dramatically reduces viral titers. Most importantly, APOBEC3 knockout mice are more susceptible to MMTV and MLV infection compared to their wild type littermates. These findings indicate that the APOBEC3 provides protection to mice against retroviral infection and represent the first demonstration that it functions during retroviral infection in vivo. We are currently studying how genetic variation in the mouse APOBEC3 genes affects their ability to inhibit infection and whether APOBEC3 can be used as an anti-retroviral therapeutic target.
We have recently extended our studies to new world arenaviruses like Junín virus. These viruses are endemic in new world rodents in South America and are spread to humans via aerosolization. Interestingly, both Junín virus and MMTV use transferrin receptor 1 (TfR1) for entry. We are currently studying how MMTV and Junín virus use TfR1 to enter cells and how the iron metabolic pathway intersects with infection by these viruses. In addition, we are studying different host genes that confer resistance or susceptibility Junín virus, and whether polymorphisms in these genes in humans alter infection. These studies will help us identify host molecules involved in cell- and disease-tropism and help us to develop new anti-viral therapies.
My laboratory is particularly interested in understanding how angiogenesis inhibitors act to limit endothelial cell activation and angiogenesis, and how they might be used therapeutically to treat cancers. Specific projects include:
i) Understanding why Down syndrome individuals are protected against cancer and the role of the calcineurin inhibitor, DSCR1 in suppressing VEGF-mediated angiogenesis;
ii) Identifying new cell extrinsic tumor suppressor functions of p53 and p19ARF: regulation of the endogenous angiogenesis inhibitors thrombopsondin-1 and endostatin;
iii) Investigating a novel role for the endogenous angiogenesis inhibitor thrombospondin-1 in mediating oncogene-induced senescence;
iv) Immune surveillance and the role of the endogenous angiogenesis inhibitors thrombospondin-1 and endostatin in tumor immunity.
My lab is interested in uncovering molecular and cellular mechanisms used by the host to defend itself against bacterial pathogens and how bacterial pathogens evade or manipulate host defenses.
We utilize the intracellular bacterial pathogen Legionella pneumophila, causative agent of the severe pneumonia Legionnaires' disease, as our primary model. Legionella has evolved numerous mechanisms for modulating eukaryotic processes in order to facilitate its survival and replication within host cells. The ease with which Legionella can be genetically manipulated provides a powerful system for dissecting immune responses to bacteria that differ in defined virulence properties and for elucidating mechanisms of bacterial pathogenesis.
A major focus of our lab involves understanding how the immune system distinguishes between virulent and avirulent bacteria and tailors appropriate antimicrobial responses against virulent bacteria. One key immune pathway involves the inflammasome, a multi-protein cytosolic complex that activates the host proteases caspase-1 and caspase-11 upon cytosolic detection of bacterial products. These caspases mediate the release of IL-1 family cytokines and other inflammatory factors critical for host defense, but overexuberant activation can lead to pathological outcomes such as septic shock. We are currently pursuing how inflammasomes are differentially regulated in mice and humans in response to bacterial infection, as mice and humans differ in several key inflammasome components.
We are also uncovering how the immune system successfully overcomes the ability of pathogens to suppress host functions critical for immune defense. We recently found that infected macrophages circumvent the ability of Legionella to block host translation by synthesizing and releasing key cytokines that instruct bystander uninfected cells to generate an effective immune response. We are defining additional mechanisms that mediate communication between infected and bystander cells and promote eventual control of bacterial infection. We also examine immune responses to other bacterial pathogens with the goal of identifying shared and unique features of innate immunity and bacterial virulence. Insight into these areas will advance our understanding of bacterial pathogenesis, how the innate immune system distinguishes between virulent and avirulent bacteria and initiates antimicrobial immunity, and will ultimately aid in the design of effective antimicrobial therapies and vaccines.
The work in my laboratory is centered on the core binding factor (Runx1-CBFβ) and its roles in hematopoietic stem cell (HSC) formation and function. We study how HSCs form in the embryo, the step at which HSC formation is dependent on Runx1-CBFβ, the biochemical functions of Runx1-CBFβ, and how mutations in the genes encoding Runx1-CBFβ generate pre-leukemic stem cells. A more recent line of investigation is to determine the role of inflammatory signaling in HSC formation.
Broadly, the lab studies the development and physiology of the mammalian brain. One goal is to define the systems that contribute to specific behaviors, and to understand the mechanisms that underlie these behaviors. Such knowledge may ultimately permit the prevention and treatment of mental illness. Gene-targeting allows the analysis of specific genetic alterations in the context of the whole organism. The ability to add, delete or modify genes is particularly useful in the analysis of complex organ systems such as the brain, where half of all genes are thought to be uniquely expressed.
The lab focuses on the adrenergic nervous system in which norepinephrine (NE) and epinephrine are the classic neurotransmitters. By genetically eliminating the biosynthetic enzyme for NE, dopamine beta-hydroxylase (DBH), mutant mice (Dbh-/-) that completely lack NE and epinephrine were created. These mice are conditional mutants in that NE can be restored to the adrenergic terminals by supplying a synthetic amino acid precursor of NE, L-DOPS. The lab is pursuing several fundamental observations that resulted from the creation of these mutant mice. These include the roles of NE in learning and memory, as well as the neuronal physiology and signaling that underlie these effects. They also include the role of NE in the effects of stress. For each of these, potentially important interactions with other transmitters and hormones is also being explored. Finally, Dr. Thomas is pursuing several novel genetic approaches for producing complementary models to the Dbh-/- mice toward a more complete understanding of CNS adrenergic function.
The primary focus of research in the Abel lab is to understand the cellular and molecular mechanisms of long-term memory storage with a focus on the mammalian hippocampus. One of the hallmarks of long-term memory storage is that it requires the synthesis of new genes and new proteins, which act to alter the strength of synaptic connections within appropriate neuronal circuits in the brain. How are the various signals acting on a neuron integrated to give rise to appropriate changes in gene expression? How are changes in gene expression maintained to sustain memories for days, months and even years? In our lab, we have focused on transcriptional co-activators such as CREB-binding protein (CBP) and p300, leading us to investigate the effects of histone acetylation and other epigenetic modifications in memory storage. Increasing histone acetylation pharmacologically by inhibiting histone deacetylase (HDAC) enzymes during memory consolidation enhances long-term memory. Of particular importance is the identification of genes regulated by epigenetic mechanisms during memory consolidation and after HDAC inhibition using next-generation sequencing technology. Signals from synapses drive the transcriptional processes that are required for memory storage. A major challenge in the study of these synaptic signals is how the pathway specificity of synaptic plasticity is maintained in the face of diffusible second messengers, such as cyclic AMP (cAMP), and diffusible proteins, such as the catalytic subunit of protein kinase A (PKA). We are investigating the role of A-kinase anchoring proteins (AKAPs), which restrict PKA to specific subcellular locations, to define how signal transduction pathways in neurons are able to exhibit spatial specificity.
We are also investigating processes that can modulate the consolidation of long-term memory. For example, the biological function of sleep has remained elusive, but studies suggest that one function of sleep may be to mediate memory storage. First, sleep appears to facilitate the formation of hippocampus-dependent memories, and sleep is increased following training. Second, sleep appears to be regulated by many of the same molecular processes that contribute to memory storage, including the transcription factor cAMP response element-binding protein (CREB) and the PKA signaling pathway. By using conditional genetic approaches and gene expression studies, we are striving to elucidate the machinery underlying sleep/wake regulation and define the role of sleep in the consolidation of long-term memory. Our studies also reveal that sleep deprivation impairs memory consolidation and synaptic plasticity by impairing signaling through the cAMP pathway.
Cognitive deficits accompany many neurological, psychiatric and neurodevelopmental disorders. We are interested in determining how our knowledge of the cellular and molecular mechanisms of synaptic plasticity and memory storage can help us understand the cognitive deficits that are seen in patients with schizophrenia, autism and intellectual disability. Recent evidence suggests that disturbances in specific intracellular signaling pathways may contribute to schizophrenia. Studies in humans indicate that activity within the cAMP/PKA signaling pathway may be increased in the central nervous systems of schizophrenia patients, and our work suggests that this pathway plays a role in endophenotypes of schizophrenia in mice. With these translational approaches, we hope to identify novel targets for the development of new therapeutics to treat psychiatric and neurodevelopmental disorders.
In our lab we study two cognitive disorders: Fragile X Mental Retardation and Alzheimer's disease. To study these disorders we utilize Drosophila models. These models are mutants of the Drosophila homologues of the humans genes associated with these disorders. With these models we are investigating the biochemical functions and biochemical pathways affected by the loss of the disease related proteins that cause phenotypes that are similar to symptoms display by patients of these diseases (see below). Our goals are to gain insight into the underlying causes of the respective disease symptoms as an approach to develop therapeutic strategies to treat these disease as well as to learn more about the basic mechanisms required for normal learning and memory.
Research currently centers on molecular mechanisms of neuron dysfunction, degeneration and death in normal aging and in neurodegenerative diseases (Alzheimer's and Parkinson's disease, frontotemporal dementias with/without parkinsonism, motor neuron disease, etc.). This research uses immunological, biochemical, genetic, molecular and morphological methods to study human CNS and PNS tissue samples (postmortem or surgical), cell lines, synthetic proteins, and transgenic models of neurodegenerative diseases. Dr. Trojanowski is involved in collaborative initiatives between PENN Medicine and the University of Pennsylvania School of Nursing to advance drug discovery, clinical research, and patient care related to Alzheimer’s disease and the Alzheimer's Disease Neuroimaging Initiative (ADNI) to test whether serial magnetic resonance imaging, positron emission tomography, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer's disease.
The central aim in my lab is to understand the genetic, biological, and evolutionary basis of metabolic, cardiovascular, and immune-mediated phenotypes in human populations. To build this understanding, the lab constructs computational and statistical tools grounded in principles of population biology and quantitative genetics and apply them to genetic data collected across thousands of entire human genomes.
My research has answered population genetic questions about recent demographic and selective events in human populations, and more recently I have focused on mapping risk alleles for common diseases, particularly type-2 diabetes and heart attack. I have also contributed to novel statistical approaches for population genetic inference and disease mapping studies, as well as leading the development of next generation sequencing and genotypic assay technologies designed to improve characterization of genetic variation in the human genome.
In the coming years, the lab activities will focus on developing informational and statistical tools which interrogate vast quantities of human genetic association data, together with other important information sources -- gene expression, protein-protein networks, Chip-SEQ, text-mining, epidemiology, and multiple phenotypic measurements in humans -- in order to construct credibly actionable information on pathways responsible for disease susceptibility.
The Vonderheide laboratory combines efforts in both basic research and clinical investigation to advance the understanding of tumor immunology and to develop novel immunotherapies for cancer. The chief hypothesis is that successful approaches in tumor immunotherapy will need to (a) optimize target antigens with regard to clinical applicability and risk of antigen loss, (b) repair host immuno-incompetence in antigen presentation and T cell function, and (c) circumvent immuno-suppressive factors of the tumor and tumor microenvironment.
Our lab focuses on Alzheimer’s disease and other neurodegenerative disorders, aging, and psychiatric disorders including autism and bipolar disorder. Ongoing projects in our lab can be divided into the following three main directions:
• Genetics and genomics of Alzheimer’s disease and other neurodegenerative disorders.
• Informatics and algorithm development for genome-scale experiments.
• Biomarker development for aging and neurodegenerative disorders.
My lab studies coronavirus pathogenesis. We use murine coronavirus, mouse hepatitis virus (MHV) infection of mice as a model system for the study of: 1) acute viral encephalitis; 2) chronic demyelinating diseases such as Multiple Sclerosis and 3) virus-induced hepatitis. We have the important tools of a well-developed animal model system and two reverse genetic systems with which to manipulate the viral genome. Human coronaviruses are primarily respiratory viruses, and include the common cold viruses OC43 and 229E as well as the emerging viruses MERS and SARs that cause severe and life threatening diseases. We are beginning to study human coronavirus interactions with respiratory tract cells. Our long-term goal is to elucidate the viral and cellular determinants of coronavirus tropism and pathogenesis in the brain, the liver and the lung. Much of our current work focuses on coronavirus-encoded antagonists of type I interferon, specifically virus-encoded phosphodiesterase that antagonize the OAS-RNase L pathway. Another direction in our lab is the study of the role of inflammasome related cytokines in viral clearance as well as both acute and chronic MHV induced disease.
The Weljie Lab is located in the Department of Pharmacology at the University of Pennsylvania. Our lab is at the forefront of metabolomics technologies to examine biological problems in a translational medicine context.
Metabolomics is a growing sub-field of systems biology centered on the study of small biological molecules in biological fluids and tissues. Recent research suggests that analysis of metabolite concentrations in living systems is useful in disease diagnosis, prognosis, and predicting drug efficacy in a personalized medicine context.
Our focus is on developing analytical methods to advance research in translational medicine. There is an intrinsic link between metabolism and function of the innate circadian clock system in numerous organisms and disease states, but the exact mechanism by which the clock controls mammalian metabolism is poorly understood. Our work seeks to fill this knowledge gap along with identifying biomarkers of cancer and environmental health.
A major goal of the research in Dr. Wherry's laboratory is to understand the mechanisms of T cell exhaustion during chronic infections and cancer. Our work studying CD8 T cell responses during chronic viral infections has demonstrated that virus-specific CD8 T cells often lose effector functions and fail to acquire key memory T cell properties (i.e. become exhausted). Using approaches including high dimensional flow cytometry, transcriptional and epigenetic profiling and in vivo models we are defining cellular pathways involved in T cell exhaustion and normal memory T cell differentiation. Some areas of considerable current interest for the lab include inhibitory receptors (e.g. PD-1, LAG-3), transcription factors and inflammatory pathways. Blockade of inhibitory receptors such as PD-1 (i.e. checkpoint blockade) is now a major therapeutic approach in human cancer. Ongoing studies are examining the mechanisms of these blockades in preclinical models as well as in humans and are investigating the next generation of immune targets to reverse T cell exhaustion. In addition to T cell exhaustion, the laboratory has major interests in the biology of human T follicular helper cells (TFH). Our studies are interrogating the pathways controlling optimal TFH responses following human vaccination. Finally, additional interests in the lab include intestinal novovirus infection, respiratory infections and co-infections.
The research programs in the Wu laboratory focus on the mutualistic interactions between the gut microbiota and the host with a particular focus on metabolism. Growing evidence suggests that diet impacts upon both the structure and function of the gut microbiota that, in turn, influences the host in fundamental ways. Current areas of investigation include the effect of diet on the composition of the gut microbiota and its subsequence effect on host metabolism related to nitrogen balance as well as its impact on metabolic pathways in the intestinal epithelium, principally fatty acid oxidation. Through a UH3 roadmap initiate grant, he is helping to direct a project investigating the impact of diet on the composition of the gut microbiome and its relationship to therapeutic responses associated with the treatment of patients with Crohn’s disease using an elemental diet. Finally, Dr. Wu is leading a multidisciplinary group of investigators using phosphorescent nanoprobe technology to examine the dynamic oxygen equilibrium between the host and the gut microbiota at the intestinal mucosal interface.
Found 62 laboratories .