Type 1 Diabetes Mouse Resource (T1DR)

1 型糖尿病小鼠资源 (T1DR)

• 批准号: 8435054
• 负责人: David V Serreze
• 金额: $ 250万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435054
• 关键词: Ablation; Address; Alleles; Area; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Cell Transplants; Cells; Communities; Development; Disease; Engraftment; Epidemiologic Studies; Generations; Genes; Genetic Variation; Genomics; Goals; Health Status; Human; Human Genetics; IL2 gene; IL4 gene; IL7 gene; IL9 gene; Immune; Immune system; Immunocompetent; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin 2 Receptor Gamma; Interleukin-15; Intervention; Islets of Langerhans; Learning; Life; Lymphocyte; Lymphoid; Mediating; Mission; Mus; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Killer Cells; Pancreas; Pathogenesis; Patients; Population; Predisposition; Recommendation; Research; Research Personnel; Resistance; Resources; Series; T-Lymphocyte; Testing; The Jackson Laboratory; Tissues; Validation; autoreactive T cell; base; clinically relevant; genetic manipulation; human leukocyte antigen gene; human tissue; in vivo; interleukin-21; mouse model; operation; prevent; receptor; symposium; tumorigenesis

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.

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(Jackson)建立的1型糖尿病小鼠资源(T1DR)的努力。到目前为止，T1DR的任务是进口、管理、进行基因和表型验证、冷冻保存和分发被认为对T1D研究重要的现有小鼠种群。此次续签申请的具体目标1就是继续这种努力。然而，我们的目标也是在几个方面扩大T1DR的努力。其中一个扩展领域将集中在T1D研究的“人性化”小鼠储备上。其中包括一系列纯合的NOD背景小鼠，无论是SCID突变还是rag1零突变，消除内源性淋巴细胞与编码IL2、IL4、IL7、IL15和IL21受体的共同伽马链成分的基因的失活变体相结合，导致NK细胞的消融，并防止缩短寿命的淋巴样肿瘤的发生。这些基因操作的综合效应使这些菌株(分别命名为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。随着更多人类遗传成分的引入，这种NSG和NRG菌株的用途不断扩大，例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抵抗力相关的各种HLAI和II类等位基因。携带疾病相关基因的免疫活性NOD小鼠在识别与人类T1D发育相关的自身反应性T细胞群方面也被证明是有用的。继续对NOD、NSG和NRG小鼠进行基因组优化，以优化其免疫系统的人性化，不仅是为了筛选糖尿病效应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，T1DR的具体目标2是追求一个新的目标，即基于外部用户社区的建议，生产和/或完善额外的T1D相关小鼠种群，重点放在那些允许在体内测试人类组织和细胞的小鼠种群，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背景库阵列，这些背景库可用于解决人类T1D发病机制的各个方面，外部研究社区将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BOH网络研讨会和杰克逊的现场会议，提供途径，使研究界能够更好地了解可用于研究人类T1D发育的各种病理成分的小鼠模型的可用性、用途和局限性。好了！ 公共卫生相关性：1型糖尿病(T1D)是一种威胁生命的疾病，当大量基因之间的相互作用导致T淋巴细胞的产生，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T1D致病基础的大部分知识都来自于对一系列不断扩大的与疾病相关的小鼠模型的分析。其中包括小鼠模型，在该模型中，T1D相关的自身免疫反应由遗传编码的分子和/或人类来源的移植细胞介导。由于后勤和费用的原因，对于大多数研究人员来说，很难持续保持完整的小鼠模型，这些模型可能被用来解决关于T1D基础的各种问题，和/或向其他研究人员提供这些库存。因此，这项提议的目标是继续在杰克逊实验室(Jackson)运营1型糖尿病小鼠资源(T1DR)。T1DR的任务是进口、重新衍生到高水平的健康状态，管理、基因和表型验证、冷冻保存和向T1D研究社区分发有价值的小鼠库存。