NATIONAL GNOTOBIOTIC RODENT RESOURCE CENTER

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。描述(由申请人提供)：这项修订申请要求扩大现有的、由经验丰富的科学家运营的高效啮齿动物生理学单位，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。这些灵知生菌小鼠和大鼠将被用来研究在这个复杂生态系统中以共生细菌群或单个组件定植正常和基因突变宿主的生理和病理生理学后果。常用的野生型小鼠和大鼠品系将用于研究各种组织和免疫细胞的发育、分化和适应的生理学研究，而基因工程小鼠(基因敲除和转基因)和近交系小鼠和大鼠易患各种炎症性和肿瘤性疾病(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。这些啮齿动物将被衍生到无菌(无菌)条件下，并将保持无菌繁殖群体。这些生理过程或疾病的发病率和侵袭性将在无菌、明确的菌群(与一种或多种细菌单联或共生)、无特定病原体或常规条件下进行研究。可以通过几种机制获得用于研究的组织：诺生菌啮齿类动物可以被运往调查人员进行研究，调查人员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本运送给提出要求的调查人员。这些研究将准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。创新研究包括通过胚胎移植优化无菌小鼠品系的无菌衍生，以及研究细菌诱导免疫介导性结肠炎的机制。申请者在维护和研究无菌和单一相关的大鼠和小鼠方面拥有相当丰富的经验，进行了关键观察，证明了非致病共生细菌在免疫介导的慢性肠道炎症中的重要作用，并证明了在啮齿动物的无菌衍生、胚胎移植和冷冻保存方面的专业知识。该单元旨在补充和扩展由NCRR资助的北卡罗来纳大学突变鼠区域资源中心，以节省成本，并最大限度地提高效率和利用这两个设施。申请者附上了来自全国所有地区的至少29个机构的75名调查人员的承诺书，其中包括2个NIH内部项目的成员。这些跨学科的用户或感兴趣的研究人员研究各种各样的生理过程和疾病模型，并得到了多个美国国立卫生研究院、资深S政府和美国克罗恩S和结肠炎基金会的资助。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.