This revised application requests expansion of an existing, highly productive rodent gnotobiotic unit run by experienced scientists to provide a national resource for NIH-funded investigators to explore genetic/environmental interactions. These gnotobiotic mice and rats will be used to investigate the physiologic and pathophysiologic consequences of colonizing normal and genetically mutated hosts with commensal bacterial flora or with individual components of this complex ecosystem. Commonly used wild-type murine and rat strains will be available for physiologic studies investigating the development, differentiation and adaptation of various tissues and immune cells, while genetically engineered mice (knockout and transgenic) and inbred mice and rats susceptible to various inflammatory and neoplastic diseases (enterocolitis, colon cancer, diabetes, atherosclerosis, periodontal disease, arthritis, lupus, psoriasis, sexually transmitted diseases etc.) will be available to study disease pathogenesis. These rodents will be derived into sterile (germ-free) conditions and germ-free breeding colonies will be maintained. These physiologic processes or the incidence and aggressiveness of disease will be studied under germ-free, defined flora (monoassociated or cocolonized with 1 or more bacterial species), specific pathogen free or conventional conditions. Tissues can be obtained for study by several mechanisms: gnotobiotic rodents can be shipped to investigators for study, investigators can visit the facility to perform necropsies, or facility technicians can process tissues and cells on site, then ship samples to requesting investigators by overnight express mail. These studies will precisely determine the influence of various constituents of normal bacteria on disease pathogenesis and physiologic processes, suggest new therapeutic targets, identify protective organisms, and provide new scientific opportunities for investigators by opening new areas of research. Innovative studies to optimize sterile derivation of germ-free mouse lines by embryo transfer and to investigate mechanisms of bacterial induction of immune mediated colitis are included. The applicants have considerable experience in maintaining and investigating germ-free and monoassociated rats and mice, have made pivotal observations demonstrating the essential role of nonpathogenic commensal bacteria in chronic, immunologically-mediated intestinal inflammation, and have documented expertise in sterile derivation, embryo transfer and cryopreservation of rodents. This unit is designed to complement and extend the NCRR-funded UNC Mutant Mouse Regional Resource Center to conserve costs and to maximize efficiency and use of both facilities. The applicants have attached letters of commitment from over 75 investigators from at least 29 institutions, from all geographic regions of the country and include members of 2 intramural NIH programs. These interdisciplinary users or interested investigators study a wide variety of physiologic processes and disease models and are funded by multiple NIH institutes, the Veteran's Administration and the Crohn's and Colitis Foundation of America.
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