Research in my laboratory is focused on the development of mouse models for identifying genes controlling complex human diseases, particularly those resulting from abnormalities of the immune system. Using both linkage analyses and classical recombinational genetics, we have localized such genes in three distinct models of autoimmunity, including insulin-dependent (“juvenile”) diabetes, systemic lupus erythematosus, and Crohn’s-like inflammatory bowel disease. We are currently using molecular and computational approaches, as well as detailed studies of immune function, to define the structural differences in disease-associated alleles and to characterize their function in both mice and humans.<\/p>\n
Type 1 diabetes (T1D):<\/p>\n
T1D results from T cell-dependent inflammatory destruction of insulin-producing pancreatic islet cells. Our studies have shown that the development of full-blown disease requires sequential expression of defects in antigen presentation to T cells, control of T cell activation to self antigens from the islets, and the response of pancreatic islet cells to the resulting local inflammation initiated by self-antigen-specific T cells. Each step in the disease process can be controlled by a unique set of genes, resulting in an extremely complicated polygenic susceptibility. However, disease can be blocked by normalizing gene function at several discrete steps. We have identified abnormalities in key regulatory genes that control the differentiation and activation of both CD8+ T cells and myeloid antigen presenting cell subsets (macrophages and dendritic cells) in non-obese diabetic (NOD) mice, a well-established model of human T1D. These genes include a member of the Runt family of transcriptional regulators, as well as key members of the GM-CSF signaling pathway. Current work in the laboratory seeks to identify the specific targets of these genes that are required for maintaining normal tolerance in the T cell population and preventing the development of organ-specific autoimmune disease. We are also testing whether the same pathways are defective in human T1D and attempting to identify small molecule inhibitors and activators of these gene products as potential therapeutic agents.<\/p>\n
Systemic lupus erythematosus (SLE):<\/p>\n
In SLE, T cells appear to interact with B cells to produce antibodies that recognize self nuclear polynucleotide\/protein antigens. Immune complexes, formed when such antibodies interact with circulating debris from necrotic or apoptotic cells, deposit in tissues and induce inflammatory damage in kidneys, skin, and other target organs. Using the NZM2328 mouse, an inbred model of human SLE, we have localized two genes which control the development of pathological autoantibodies and target damage to the kidney. We are currently attempting to identify these genes by traditional positional cloning methods and by functional characterization of the effector cell populations.<\/p>\n
Crohn’s disease (CD)<\/p>\n
We have also completed a genetic analysis of a new spontaneous mouse model of inflammatory bowel disease, the SAMP1\/Yit mouse. Although T lymphocytes may play a significant role in the initiation or progression of CD, it is clear that the innate immune system and the intestinal epithelial cells themselves are the most important factors in the development of this disease, allowing us to contrast the genetic susceptibility in this disorder with those for SLE and T1D. We have recently demonstrated that rare variants of the peroxisome proliferator-activated receptor gamma (PPAR-g) can block genetic predisposition to Crohn’s disease in both humans and mice. PPAR-g has been shown to down-regulate inflammatory responses, and loss of PPAR-g expression in mouse models is associated with rapid induction of destructive intestinal inflammation in response to chemical or immunological damage. Using the SAMP1\/Yit mouse, we were able to show that protective alleles of PPAR-g are characterized by high levels of expression in the crypts of the small intestine. This tissue contains the essential stem cell populations for continuous repopulation of the absorptive and protective mature epithelial cells. We are currently determining the mechanism by which this crypt-specific expression controls disease susceptibility and investigating several promising therapeutic strategies for enhancing protective levels in individuals genetically susceptible to development of CD.<\/p>\n
Techniques routinely used in our laboratory include polymerase chain reaction amplification of DNA (PCR), methods for quantifying gene expression, enzyme-linked immunosorbant assays (ELISA), flow cytometry, and cell culture, as well as computational methods for performing linkage analysis and sequence comparisons.<\/p>\n
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Additional Responsibilities & Affiliations:<\/strong>
Advisor, Medical Microbiology
Pediatric Endocrinology\/Diabetes
Director, DERC Mouse Genetics Core<\/p>\n","protected":false},"featured_media":1735484,"template":"","meta":{"_acf_changed":false,"inline_featured_image":false,"_links_to":"","_links_to_target":""},"otheraff":[],"phd-degree":[],"primary":[2327],"research-discipline":[],"research-opportunity":[],"training-grant":[],"class_list":["post-1735425","faculty-listing","type-faculty-listing","status-publish","has-post-thumbnail","hentry","primary-microbiology-immunology-and-cancer-biology"],"acf":[],"yoast_head":"\n