Gustavo D. Aguirre, VMD, Ph.D., Professor of Opthalmology
Inherited retinal degeneration disease: This laboratory studies the inheritance of retinal degeneration in dogs as a model for human diseases. These include efforts to identify the genes and locate the mutations associated with several separately inherited forms of progressive retinal atrophy (PRA), a significant disease of dogs that is also the genetic analog of retinitis pigmentosa, a group of retinal degenerations inherited in human families. This laboratory is involved in the construction of the dog genome map and is also using genomics analysis to map behavioral traits in canids.
David Artis, Ph.D., Professor of Immunology & Microbiology
Regulatory mechanisms controlling immune cell homeostasis: The long-term goals of the Artis lab are to understand the regulatory mechanisms that control immune cell homeostasis at barrier surfaces. Employing diverse models of microbial colonization, pathogen infection and chronic inflammation, we are examining how innate and adaptive immune responses are regulated in the skin, lung and intestine. Over the last fifteen years, Artis has developed expertise in examining how microbe-specific T helper cell responses develop and are regulated following infection.
Michael L. Atchison, Ph.D., Professor of Biochemistry
Understanding basic gene function: The laboratory is interested in the molecular mechanisms responsible for transcriptional regulation and the control of differentiation. Chromatin structure and histone acetylation are also important components of gene regulation. Other studies are directed towards transcriptional activation, transcriptional repression, and association with the nuclear matrix. These basic studies on gene regulation are conceptually important for understanding normal gene function, developmental disorders, and control of transferred genes in specific cell types.
Narayan G. Avadhani, Ph.D., Professor of Biochemistry
Nuclear and mitochondrial gene interaction: The research in this laboratory is focused on understanding the nature of biochemical and genetic signals which accurately coordinate the expression of the 16 kb mitochondrial genome and a number of tissue specific, as well as ubiquitously expressed, genes that encode various mitochondrial proteins in animal cells. Recent studies indicate that mitochondrial functions are critical in the pathogenesis of neurodegenerative conditions such as Alzheimer’s disease.
Tracy L. Bale, Ph.D., Professor of Neuroscience
Understanding diabetes and obesity: The laboratory's research applicable to the DERC is focused on understanding the central programming and pathways underlying a predisposition to diabetes and obesity. We have developed mouse models examining maternal obesity, caloric restriction, and chronic stress to determine target genes and epigenetic mechanisms involved in disease.
Kendra K. Bence, Ph.D., Professor of Neuroscience
Understanding diabetes and obesity: The goal of our research is to examine the cellular mechanisms by which protein tyrosine phosphatases regulate obesity and diabetes. Currently, we are investigating how tissue-specific protein tyrosine phosphatase 1B (PTP1B)-deficiency mediates effects on body weight and insulin sensitivity. PTP1B is an important negative regulator of both the insulin and leptin signaling pathways in tissues such as liver, muscle and brain. PTP1B-/- mice are lean and have increased energy expenditure, as well as improved glucose homeostasis. We hypothesize that some of the phenotypes seen in PTP1B-/- mice are due to leptinindependent effects.
Jean Bennett, M.D., Ph.D., Professor of Ophthalmology
Gene therapy retinal diseases: This laboratory studies gene therapy approaches to eye diseases, particularly the retina. In collaboration with Dr. Aguirre’s group, they performed the first successful gene therapy for an inherited blindness in a dog model. Those studies were the basis for proposing a clinical trial. Additional studies focus on diseases causing abnormal blood vessel growth, such as diabetic retinopathy and retinopathy of prematurity. The laboratory is also using somatic gene transfer to develop animal models for other specific blinding diseases and to develop methods of rescuing vision.
Ralph L. Brinster, V.M.D., Ph.D., Professor of Physiology
Biology of reproductive cells: The research in this laboratory is directed towards understanding the fundamental events involved in germ cell development and differentiation. A seminal accomplishment was the development of methods for germ-line gene transfer, which has been used to elucidate fundamental mechanisms of gene expression and the roles of genes in development and differentiation. The research currently focuses on the biology of the spermatgonial stem cell, which is responsible for the continuity of spermatogenesis in the adult male.
Michael Cancro , Ph.D., Professor of Pathology and Laboratory Medicine
B lymphocyte development: This laboratory studies innate mechanisms of B-cell immune responses. They are interested in how the innate immune system develops, how it functions in response to pathogenic organisms, and how it changes with age. Work from this laboratory has defined the developmental stages spanning immature B cell formation in the bone marrow to final maturation in the periphery and now focuses on the molecular basis for survival and differentiation within developmental subsets. Normal and mutant mice are used in the studies that focus on specific receptor systems and how age-related alterations in both intrinsic and micro-environmental factors affect innate immunity.
Peter J. Felsburg, V.M.D., Ph.D., Professor of Immunology
Inherited defects of the immune system: This laboratory studies inherited defects of the immune system. Clinical research in the WFG-CCMG led to the discovery of a form of severe congenital immune deficiency with X-linked recessive inheritance in the dog. The dog disease involves the same gene as that involved in human X-SCID, the most common form of inherited immune deficiency in children. The model is being used to study basic questions of immune system development, as well as potential treatments such as bone marrow transplantation and gene therapy.
Nigel W. Fraser, Ph.D., Professor of Microbiology
Molecular mechanisms of herpesvirus latency: The research in this laboratory is directed towards understanding the mechanism of herpes simplex virus latency and reactivation. There is also interest in the use of herpes viruses as a vector for gene therapy in the CNS, which is being done in collaboration with Dr. Wolfe. Studies using replication restricted HSV as a therapy for tumor destruction are also being performed. All of these strategies are potentially useful in clinical veterinary medicine as well as human patients.
Kurt David Hankenson, D.V.M., Ph.D., Professor of Cell Biology
Gene-targeted and transgenic murine models: This laboratory has extensive experience working with gene-targeted and transgenic murine models and in the cellular and molecular aspects of osteoblastogenesis. Dr. Hankenson’s laboratory studies the regulation of mesenchymal progenitor differentiation and maintenance of progenitor cell stemness, focused primarily on extracellular mediators of osteoblast differentiation (growth factors and ECM). His work is particularly focused on the contribution of mesenchymal-derived cells to bone regeneration and maintenance of bone formation to build and maintain adult bone mass.
Mark E. Haskins, V.M.D., Ph.D., Professor of Pathology
Lysosomal storage diseases: This laboratory focuses on lysosomal storage diseases. The WFG-CCMG has identified animal models of several of these disorders, each involving a separate enzymatic defect. The animals are accurate models of the human diseases and have provided significant new insights into the natural history and mechanisms of pathogenesis. The primary interest of this laboratory is in the pathology and treatment of bones, joints and visceral organs. The animal models have been used extensively for experiments in bone marrow transplantation, enzyme replacement, and gene therapy.
Katherine A. High, M.D., Professor of Pediatrics
Molecular biology of hemophilia: This laboratory studies hemophilia B, caused by deficiency of clotting factor IX. Successful gene therapy experiments in the dog model provided the basis for initiating human clinical trials. However, obtaining therapeutic levels in human patients has been elusive. Other dog models exist with different mutations that are especially valuable to study as counterparts to human patients, particularly for the immune response (mis-sense CRM-positive vs. nonsense CRM-negative mutations) to better understand the response to gene-transferred clotting factors.
Christopher A. Hunter, Ph.D., Professor of Pathology
Host immune responses to Toxoplasma gondii: This laboratory studies host-pathogen interactions through both innate and adaptive immunity. They focus on host responses to the parasite Toxoplasma gondii, which is an important opportunistic infection in immuno-compromised patients. Studies are directed at early post-infection events of innate immune mechanisms, at understanding how protective adaptive immunity is mediated in the brain, and understanding the importance of different intra-cellular signaling pathways in controlling the immunity.
Andras M. Komaromy, Dr.med.vet., Ph.D., Professor of Ophthalmology
Gene therapy of cone photoreceptor: This group is working on the study of molecular and cellular disease mechanisms and gene therapy of cone photoreceptor. This work is being supported by the grant R01-EY019304. Trainees enrolled in the program will be involved in all aspects of our research.
Gary A. Koretzky, M.D. Ph.D., Professor of Pathology and Laboratory Medicine
Signal transduction in immune cells: This laboratory focuses on understanding the important role T lymphocytes and other cells of the immune system play in combating infection and destroying cancerous tissue. Through specific receptors on their surface, these cells recognize infected or transformed malignant tissue. This recognition stimulates those receptors on the immune cells, initiating a cascade of biochemical events, the process known as signal transduction.
Carolina B. Lopez, Ph.D., Professor of Pathobiology
Innate immune response to virus infection: Our laboratory studies the innate immune response to virus infection. We have contributed to the understanding of the immune response to influenza and Sendai virus and of the mechanisms that govern viral recognition by immune cells. We have extensive experience using the influenza and Sendai virus models of infection in mice. We recently demonstrated that during the early phase of the anti-viral immune response to respiratory viruses the lung interacts with cells localized in the distal bone marrow to coordinate the appropriate response.
Phillip A. Scott, Ph.D., Professor of Immunology
Spectral immunity: This laboratory investigates the host factors that determine the nature of the immune response that develops after natural infection or immunization, using parasitic infection of mice as a model system. The genetic composition of the host directly influences the type of response that develops, thus different mouse strains are used to dissect the molecular mechanisms. The main focus is on cytokine regulation of host responses to infection, including evaluation of how the protective effects of cytokines can be dissociated from potential toxic effects of the molecules.
Gary Smith, D.Phil, Professor of Population Biology & Epidemiology
Epidemiology of parasitic and infectious diseases: Our laboratory studies the use of mathematical modeling techniques to facilitate the control of infectious and parasitic disease. Areas of interest include parasite population biology; the epidemiology of parasitic diseases (including those caused by viruses and bacteria); mathematical modeling of parasitic diseases of veterinary and medical importance; and economic evaluation of chemotherapeutic and vaccination strategies.
Hansell H. Stedman, M.D., Associate Professor of Surgery
Gene transfer for muscular dystrophies: This laboratory is developing novel surgical approaches to deliver genes via the vascular system to target large masses of skeletal and cardiac muscle. The goal is to treat disorders such as Duchene muscular dystrophy (DMD) and limb girdle muscular dystrophy, and cardiomyopathy. Significant progress has been made towards achieving transduction in high percentages of the muscle fibers in larger dogs. These studies are now being performed with therapeutic genes in the dog disease models to assess the physiological effects.
Charles H. Vite, DVM., Ph.D., Assistant Professor of Neurology
Imaging and pathology of neurogenetic disease: This investigator is interested in non-invasive imaging of neurological diseases using magnetic resonance imaging (MRI) methods. The laboratory has developed MR methods for quantitative measurements of dysmyelination in the Niemann-Pick C and the alpha-mannosidosis cat. Current research is directed to developing more sensitive methods to analyze pathology in the CNS, such as diffusion weighted imaging and spectroscopy. The long-term goal is to develop strategies to understand neurological diseases in situ, as well as to follow the natural progression of the diseases and responses to experimental therapies.
James M. Wilson, M.D., Ph.D, Professor of Medicine
Gene therapy in liver and lung: Dr. Wilson is interested in the development of effective gene therapies for inherited diseases, such as cystic fibrosis, muscular dystrophies, and inborn errors of metabolism in the liver and lung. Therapeutic interventions focus on the development of novel and improved somatic gene transfer methodologies. The studies utilize vectors primarily based on adeno-associated virus and other DNA viruses. This laboratory has developed a number of novel vectors by incorporating variant envelope and capsid proteins into vectors to alter their host and tissue tropism.
Beth Ann Winkelstein, Ph.D., Professor of Bioengineering & Neurosurgery
Biomechanics to animal models of pain: This group has continued to investigate the relationships between soft and neural tissue loading and pain by developing cervical models of nerve root and facet joint injury and integrating that work with tissue biomechanics. Over that period, I expanded my research to include collaborations focused on clinical diagnostics and treatments and have implemented bioengineering approaches such as small animal imaging and controlled-release of drug delivery in our models. As PI or Co-Investigator on several NIH-, NSF-, CDC-, industry-, foundation- and university-funded grants, I have integrated biomechanics and cellular biology techniques in vivo, in vitro and using cadaver, computational and human models to investigate pain mechanisms.
John H. Wolfe, V.M.D., Ph.D., Professor of Pathology
Gene therapy for the central nervous system: This laboratory investigates direct gene transfer and neural stem cell engraftment in the CNS. Various vector systems and routes of delivery are being tested using animal disease models as a platform to evaluate therapeutic effectiveness. Most of the work has centered on the lysosomal storage diseases that, like most inherited metabolic disorders in the CNS, have global lesions. Advances in treatment of the mouse CNS are being extended to the dog and cat models to study the significant scale-up barriers that must be overcome to effectively treat the human brain. This lab is also pursuing studies on reporter genes for non-invasive imaging by PET and MRI in the brain.
Margret L. Casal, Dr. med. vet., Ph.D., Assistant Professor of Medical Genetics
Inherited skin diseases: Dr. Casal is investigating inherited skin diseases. X-linked hypohidrotic ectodermal dysplasia (HED) is the most common developmental disorder affecting the skin and its appendages in humans. This laboratory is studying the genetic, molecular, and developmental basis of canine HED. Several other canine models of human genodermatoses (junctional epidermolysis bullosa, ichthyosis, black hair follicular dysplasia, and lupoid dermatosis) have also been identified in the dog, which are at various stages of characterization. These diseases provide an unparalleled group of models for investigation.
Diane Joyce Gaertner, D.V.M., Professor of Pathobiology
Laboratory Animal Medicine: The goal of this T-32 grant is to train veterinarians in research. I serve as the academic and administrative leader for laboratory animal medicine for Penn and I also lead the Division of Laboratory Animal Medicine training program for residents in laboratory animal medicine. My professional mission at this career stage is to lead a strong program of laboratory animal care and to train veterinarians in laboratory animal medicine and
research. Research education is a key component in training veterinarians to serve on a continuum between leading a research program as a PI and leading academic programs of laboratory animal care.
Urs Giger, PD Dr. med. vet., Professor of Medical Genetics
Metabolic and blood diseases: This laboratory studies inherited metabolic and blood diseases. The research focuses on the clinical, pathological, and genetic characterization of the disorders, as well as their treatment including transfusion support strategies. A major focus is the search for new models of hereditary disorders in dogs and cats, which represent homologues of human genetic diseases, including enzyme deficiencies, and blood cell and hemostatic defects. Significant effort is directed towards understanding the biochemical basis of genetic diseases and variants of mutations.
Paula S. Henthorn, Ph.D., Professor of Medical Genetics
Identification of disease causing genes: This laboratory is involved in characterizing mutations in disease causing genes in a number of large animal models, currently focused on identifying genes involved in complex patterns of inheritance. The main model is congenital heart malformations in the dog, which constitutes one of the largest classes of human birth defects. The pioneering studies of D.F. Patterson showed that the most common forms are essentially the same in humans and dogs, and are genetically determined. Studies are directed towards gene mapping, identification of specific genes in the canine model, and correlating the specific understanding of the developmental events.