FRAGILE ANIMAL MODELS OF HUMAN DISEASE

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This program proposed cellular level immunology studies in animals made unusually susceptible to ordinary non-pathogenic agents because of the nature of the research. The five interactive investigations each focus on immunology and require special gnotobiotic containment technology and disease monitoring capabilities which will be provided by core support. Project 1 uses the Severe Combined Immunodeficient (SCID) mouse as a model for the analysis mechanisms of pathogenesis and for the evaluation of intervention therapy for central nervous system listeriosis. Project 2 utilizes interleukin-2 (IL-2) deficient mice to address the mechanisms of pathogenesis of inflammatory bowel disease similar to ulcerative colitis in humans. Project 3 will exploit the similarity between human and canine lymphoietic systems and document the utility of the X-linked severe combined immunodeficiency (XSCID) dog as a model for studying human lymphopoiesis and immune function. Project 4 will explore novel approaches to the prolongation of recombinant adenovirus-mediated gene expression and the ability to readminister recombinant adenovirus in the non-human primate liver. Based on results in analogous studies in the mouse, studies will explore the feasibility of transient immunosuppression or induction of immune un-responsiveness as strategy to improve the usefulness of recombinant adenoviruses as gene therapy vectors. Project 3 proposes to characterize the role of glycoprotein A in the specific interaction of Pneumocystis carinii with host epithelial cells and to study mechanisms in which this organism mediates the severe lung injury seen with Pneumocystis carnii pneumonia, the leading cause of morbidity and mortality in patients with the Acquired Immunodeficiency Syndrome (AIDS) as well as a common life-threatening opportunistic infection in other immunocompromised patients. Senior investigators will provide valuable research mentorship to laboratory animal medicine veterinarians in postdoctoral residency training. We expect that during the proposed period of this program these studies will advance to the level of major research initiatives. We expect that during the proposed period of this program, these studies will advanced to the level of major research initiatives. The five projects are supported by a Core Unit for animal resource management, special gnotobiotic technology support, germ free isolators and high efficiency particulate air (HEPA) filtered enclosures, disease diagnostic monitoring and various research services. Interactions to data have generated gnotobiology policies and are leading to the establishment of a Center for Gnotobiology in support of research with immunocompromised animals.