National Gnotobiotic Rodent Resource Center

描述（由申请人提供）： 这项修订后的申请要求扩大现有的，由经验丰富的科学家运行的高生产率的啮齿动物gnotobiotic单位，为NIH资助的研究人员探索遗传/环境相互作用提供国家资源。这些gnotobiotic小鼠和大鼠将被用来调查的生理和病理生理后果的殖民正常和遗传突变的主机与共生细菌植物群或与这个复杂的生态系统的个别组成部分。常用的野生型小鼠和大鼠品系将可用于生理学研究，调查各种组织和免疫细胞的发育、分化和适应，而基因工程小鼠将可用于免疫学研究。（基因敲除和转基因）和近交系小鼠和大鼠易患各种炎症和肿瘤疾病（小肠结肠炎、结肠癌、糖尿病、动脉粥样硬化、牙周病、关节炎、狼疮、牛皮癣、性传播疾病等）将可用于研究疾病的发病机制。这些啮齿动物将在无菌（无菌）条件下繁殖，并保持无菌繁殖菌落。将在无菌、确定的植物群（与1种或多种细菌种属单相关或共定植）、无特定病原体或常规条件下研究这些生理过程或疾病的发病率和侵袭性。组织可以通过几种机制获得用于研究：可以将知菌啮齿动物运送给研究者进行研究，研究者可以访问设施进行尸检，或者设施技术人员可以在现场处理组织和细胞，然后通过隔夜快递将样品运送给请求的研究者。这些研究将精确地确定正常细菌的各种成分对疾病发病机制和生理过程的影响，提出新的治疗靶点，识别保护性生物，并通过开辟新的研究领域为研究人员提供新的科学机会。创新的研究，以优化无菌衍生的无菌小鼠品系的胚胎移植和研究机制的细菌诱导免疫介导的结肠炎。 申请人在维持和研究无菌和单相关大鼠和小鼠方面具有相当丰富的经验，已经进行了关键观察，证明了非致病性肠道细菌在慢性免疫介导的肠道炎症中的重要作用，并且在啮齿动物的无菌衍生、胚胎移植和冷冻保存方面具有记录在案的专业知识。该单位的目的是补充和扩大NCRR资助的突变小鼠区域资源中心，以节省成本，并最大限度地提高效率和利用这两个设施。申请人附上了来自至少29个机构的75名研究人员的承诺书，这些机构来自全国所有地理区域，其中包括2个NIH内部项目的成员。这些跨学科用户或感兴趣的研究人员研究各种生理过程和疾病模型，并由多个NIH研究所、退伍军人管理局以及美国克罗恩病和结肠炎基金会资助。

DESCRIPTION (provided by applicant): 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.