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NIDDK于2001年在杰克逊实验室（杰克逊）最初建立的1型糖尿病小鼠资源（T1 DR）的工作。到目前为止，T1 DR的使命是进口、管理、进行基因型和表型验证、冷冻保存和分发被确定为对T1 D研究重要的现存小鼠种群。本更新申请的具体目标1是继续这些努力。然而，我们的目标也是以几种方式扩大T1 DR的努力。一个这样的扩展领域将集中在T1 D研究的“人源化”小鼠种群上。这些包括一系列NOD背景小鼠scid或rag 1 null突变纯合子，消除内源性淋巴细胞与编码IL 2、IL 4、IL 7、IL 15和IL 21受体的共同γ链组分的基因的失活变体，导致NK细胞消融，并预防缩短寿命的淋巴肿瘤发生。这种遗传操作的组合效应允许这些菌株（分别命名为NSG和NRG）支持与人免疫细胞、胰岛和其他组织的高水平植入。这种NSG和NRG菌株的用途已经通过引入额外的人类遗传组分而不断扩大，例如在流行病学研究中与T1 D和其他自身免疫性疾病的易感性或抗性相关的各种HLA I类和II类等位基因。携带疾病相关HLA基因的免疫活性NOD小鼠也已证明可用于鉴定与人类T1 D发展相关的自身反应性T细胞群。需要NOD、NSG和NRG小鼠的持续基因组改进以优化其免疫系统的“人源化”，不仅筛选致糖尿病效应T细胞的存在，而且开发潜在的临床相关疾病干预方法。因此，具体目标2是T1 DR追求一个新的目标，即根据外部用户社区的建议，生产和/或完善额外的T1 D相关小鼠种群，重点关注那些允许在体内测试人体组织和细胞的小鼠种群，包括分析与T1 D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背景库存，可用于解决人类T1 D发病机制的各个方面，外部研究界将需要更好地了解其可用性，用途和局限性。为了实现这一目标，具体目标3是通过杰克逊的网络研讨会和现场会议提供途径，使研究界能够更好地了解可用于研究人类T1 D发展的各种病理成分的小鼠模型的可用性、用途和局限性。! 公共卫生相关性：1型糖尿病（T1 D）是一种危及生命的疾病，当大量基因之间的相互作用导致T淋巴细胞的产生时，所述T淋巴细胞介导胰腺内胰岛素产生细胞的异常自身免疫破坏。关于T1 D的致病基础的大部分知识都来自对不断扩大的疾病相关小鼠模型的分析。这些包括小鼠模型，其中T1 D相关的自身免疫应答由遗传编码的分子和/或人源移植细胞介导。由于后勤和费用的原因，大多数研究人员难以持续维持可能用于解决有关T1 D基础的各种问题的全部小鼠模型，和/或将这些库存提供给其他研究人员。因此，本提案的目标是继续在杰克逊实验室（杰克逊）运营1型糖尿病小鼠资源（T1 DR）。T1 DR的使命是导入、重新衍生到高水平的健康状态、策展、基因型和表型验证、冷冻保存以及向T1 D研究社区分发有价值的小鼠库存。

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.