Type 1 Diabetes Mouse Resource (T1DR)

描述（由申请人提供）：本申请的总体目标是继续由NIDDK于2001年在杰克逊实验室（Jackson）最初建立的1型糖尿病小鼠资源（T1DR）的努力。迄今为止，T1DR的任务是导入、管理、执行基因型和表型验证、冷冻保存和分发被认为对T1D研究重要的现存小鼠种群。这次续期申请的具体目的是继续这种努力。然而，我们的目标也是从几个方面扩大T1DR的工作。其中一个扩展领域将集中于用于T1D研究的“人源化”小鼠库存。其中包括一系列NOD背景小鼠的scid或rag1null突变纯合子，消除内源性淋巴细胞，结合编码IL2， IL4, IL7， IL15和IL21受体的常见γ链成分的基因失活变体，导致NK细胞的消蚀，并防止缩短寿命的淋巴细胞肿瘤发生。这些基因操作的综合效果使这些菌株（分别指定为NSG和NRG）能够支持与人类免疫细胞、胰岛和其他组织的高水平植入。随着其他人类遗传成分的引入，诸如流行病学研究中与T1D和其他自身免疫性疾病的易感性或耐药性相关的各种HLA I类和II类等位基因，这些NSG和NRG菌株的应用范围不断扩大。携带疾病相关HLA基因的免疫能力NOD小鼠也被证明可用于识别与人类T1D发展相关的自身反应性T细胞群。需要对NOD、NSG和NRG小鼠进行持续的基因组改良，以优化其免疫系统的“人源化”，这不仅是为了筛选致糖尿病效应T细胞的存在，也是为了开发潜在的临床相关疾病干预方法。因此，具体目标2是T1DR追求一个新的目标，即根据外部用户群体的建议，生产和/或完善额外的T1D相关小鼠库存，重点是那些允许在体内进行人体组织和细胞测试的小鼠库存，包括分析与T1D患者相关的自身免疫反应。为了有效地利用不断扩大的NOD、NSG和NRG背景资源，这些资源可用于研究人类T1D发病机制的各个方面，外部研究界需要更好地了解它们的可用性、用途和局限性。为了实现这一目标，具体目标3是通过网络研讨会和杰克逊现场会议，提供途径，使研究界能够更好地了解小鼠模型的可用性、用途和局限性，这些模型可用于研究人类T1D发展的各种病理成分。！

DESCRIPTION (provided by applicant): The overall goal of this application is to continue the efforts of the Type 1 Diabetes Mouse Resource (T1DR) originally established by NIDDK at The Jackson Laboratory (Jackson) in 2001. To date the mission of the T1DR has been to import, curate, perform genotypic and phenotypic validation, cryopreserve, and distribute extant mouse stocks identified as important to T1D research. Specific aim 1 of this renewal application is to continue such efforts. However, it is also our goal to expand the efforts of the T1DR in several ways. One such area of expansion will focus on "humanized" mouse stocks for T1D research. These include a series of NOD background mice homozygous for either the scid or rag1null mutations eliminating endogenous lymphocytes combined with an inactivated variant of the gene encoding the common gamma chain component of the IL2, IL4, IL7, IL15, and IL21 receptors resulting in the ablation of NK cells, and preventing life-shortening lymphoid tumorigenesis. The combined effects of such genetic manipulations allow these strains (respectively designated NSG and NRG) to support high levels of engraftment with human immune cells, pancreatic islets, and other tissues. The utility of such NSG and NRG strains has been continually broadened by the introduction of additional human genetic components, such as various HLA class I and II alleles associated in epidemiological studies with susceptibility or resistance to T1D and other autoimmune diseases. Immuno- competent NOD mice carrying disease associated HLA genes have also proven useful in identifying autoreactive T cell populations relevant to T1D development in humans. Continued genomic refinements of NOD, NSG, and NRG mice are required to optimize "humanization" of their immune systems, not only to screen for the presence of diabetogenic effector T cells, but also to develop potentially clinically relevant disease intervention approaches. Thus, specific aim 2 is for the T1DR to pursue a new goal of producing and/or perfecting, based on the recommendations of the external user community, additional T1D relevant mouse stocks with a focus on those that allow testing in vivo of human tissues and cells, including analyses of autoimmune responses of relevance to T1D patients. In order to effectively utilize the ever expanding array of NOD, NSG, and NRG background stocks that can be employed to address various facets of human T1D pathogenesis, the external research community will need to be better informed of their availability, uses, and limitations. To achieve this goal, specific aim 3 is to provide, through boh webinars and onsite conferences at Jackson, avenues enabling the research community to become better informed on the availability, uses, and limitations of mouse models that can be employed to study various pathological components of T1D development in humans. ! PUBLIC HEALTH RELEVANCE: Type 1 diabetes (T1D) is a life threatening disease that results when interactions between a large number of genes results in the generation of T lymphocytes which mediate the aberrant autoimmune destruction of insulin producing cells within the pancreas. Much of what has been learned about the pathogenic basis of T1D has come from the analyses of an ever-widening array of disease relevant mouse models. These include mouse models in which T1D relevant autoimmune responses are mediated by genetically encoded molecules and/or transplanted cells of human origin. For logistical and expense reasons, it is difficult for most investigators to continually maintain the full array of mouse models that could possibly be used to address various questions about the basis of T1D, and/or supply such stocks to other researchers. Thus, the goal of this proposal is to continue operations at The Jackson Laboratory (Jackson) of the type 1 diabetes mouse resource (T1DR). The mission of the T1DR is to import, re-derive to a high-level health status, curate, genotypically and phenotypically validate, cryopreserve, and distribute mouse stocks of value to the T1D research community.