Genetics of Virus-Induced Autoimmunity in BB Rats

BB 大鼠病毒诱导的自身免疫的遗传学

• 批准号: 6968181
• 负责人: JOHN Peter MORDES
• 金额: $ 25.55万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6968181
• 关键词: autoimmunity; bioinformatics; gene environment interaction; gene expression; gene induction /repression; genetic mapping; genetic markers; genetic screening; genetic susceptibility; genetically modified animals; genotype; immune response; immunogenetics; insulin dependent diabetes mellitus; laboratory rat; microarray technology; molecular cloning; polymerase chain reaction; proteomics; single nucleotide polymorphism; virus diseases; virus related diabetes mellitus

DESCRIPTION (provided by applicant): WHY: The cause of juvenile (type 1) diabetes is still unknown. Its expression appears to require both genetic predisposition and an environmental, probably viral, trigger. Our goal is to identify the iddm17 gene, a critical non-MHC determinant of susceptibility to autoimmune diabetes following viral infection in the BBDR rat. In clean housing, BBDR rats never become diabetic, but infection with Kilham rat virus (KRV) induces the disease in 40%. Brief exposure to a non diabetogenic dose of poly I:C, a ligand of toll-like receptor 3, before infection increases the penetrance of autoimmune diabetes to 100%. Using this induction protocol, we have discovered a new BBDR locus (Iddm17) specifically required for virus-triggered diabetes. HOW: This is a revised application of reduced scope that is focused exclusively on identifying genes in the Iddm17 interval that govern the expression of autoimmune diabetes after viral infection. It will create the critical congenic rat resources needed to achieve that goal. Specific Aim No. 1 is to create large segregating populations of (BBDR x WF)F2 rats. These will be used to complete a preliminary intercross study and genome-wide scan. Composite interval mapping will be performed and results will be used to define the Iddm17 interval for positional candidate identification in Aim 2. Specific Aim No. 2 is to use marker-assisted procedures to generate congenic rats to fine map Iddm17. In these congenic animals, other dominant diabetes susceptibility genes will not be segregating. With these resources we will seek to identify the Iddm17 gene and test the hypothesis that the response of Iddm17 during viral infection is a critical determinant of autoimmune diabetes expression. WHO: To achieve our goals, we will continue a collaborative arrangement, between a cellular biologist at the University of Massachusetts Medical School and a molecular geneticist at the Drexel University College of Medicine. Their complementary activities have generated the preliminary data that form the basis of this application. WHEN: We believe we will be able to identify the Iddm17 gene within 3 years. BOTTOM LINE: While centered on studies of diabetic rats, the importance of this proposal is its relevance to human juvenile diabetes. NIH and JDRF have established both a human type 1 diabetes genetics consortium to identify susceptibility genes and the "Triggers and Environmental Determinants in Diabetes of the Young" project. The work we propose, identifying the Iddm17 gene, has the potential to contribute importantly to the goals of both of those endeavors.

描述（由申请人提供）： 为什么：青少年（1型）糖尿病的原因仍然未知。它的表达似乎需要遗传倾向和环境（可能是病毒）触发。我们的目标是确定iddm17基因，一个关键的非MHC决定因素的易感性，以自身免疫性糖尿病病毒感染后的BBDR大鼠。在干净的饲养环境中，BBDR大鼠从未患糖尿病，但Kilham大鼠病毒（KRV）感染可诱发40%的糖尿病。在感染前短暂接触非致糖尿病剂量的poly I：C（Toll样受体3的配体）可使自身免疫性糖尿病的发病率增加至100%。使用这种诱导方案，我们发现了一个新的BBDR基因座（Iddm17），该基因座是病毒触发的糖尿病特异性所需的。 如何：这是一个缩小范围的修订应用程序，专门专注于识别Iddm17间隔中的基因，这些基因控制病毒感染后自身免疫性糖尿病的表达。它将创造实现这一目标所需的关键同类鼠资源。具体目标1是建立（BBDR x WF）F2大鼠的大分离群体。这些将用于完成初步的交叉研究和全基因组扫描。将进行复合区间标测，结果将用于定义目标2中位置候选识别的Iddm 17区间。具体目标2是使用标记辅助程序来产生同源大鼠以精细定位Iddm 17。在这些同类动物中，其他显性糖尿病易感基因不会分离。有了这些资源，我们将寻求确定Iddm17基因和测试的假设，Iddm17病毒感染期间的反应是一个关键的自身免疫性糖尿病表达的决定因素。 卫生组织：为了实现我们的目标，我们将继续合作安排，在马萨诸塞州医学院的细胞生物学家和德雷克塞尔大学医学院的分子遗传学家之间。他们的互补活动产生了初步数据，构成了这一应用的基础。 何时：我们相信我们将能够在3年内确定Iddm17基因。 底线：虽然集中在糖尿病大鼠的研究，这项建议的重要性是它与人类青少年糖尿病的相关性。NIH和JDRF已经建立了一个人类1型糖尿病遗传学联盟，以确定易感基因和“年轻人糖尿病的触发因素和环境决定因素”项目。我们提出的工作，识别Iddm17基因，有可能为这两项努力的目标做出重要贡献。