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: 7107151
• 负责人: JOHN Peter MORDES
• 金额: $ 23.48万
• 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/7107151
• 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）： 原因：青少年（1 型）糖尿病的病因仍不清楚。它的表达似乎需要遗传倾向和环境（可能是病毒）触发。我们的目标是鉴定 iddm17 基因，它是 BBDR 大鼠病毒感染后对自身免疫性糖尿病易感性的关键非 MHC 决定因素。在干净的饲养环境中，BBDR 大鼠永远不会患糖尿病，但感染 Kilham 大鼠病毒 (KRV) 会导致 40% 的大鼠患糖尿病。在感染前短暂接触非致糖尿病剂量的聚 I:C（Toll 样受体 3 的配体）可将自身免疫性糖尿病的外显率提高至 100%。使用该诱导方案，我们发现了病毒引发的糖尿病特别需要的新 BBDR 基因座 (Iddm17)。 方法：这是缩小范围的修订版应用程序，专注于识别 Iddm17 区间中控制病毒感染后自身免疫性糖尿病表达的基因。它将创造实现这一目标所需的关键同类大鼠资源。具体目标 1 是创建大量 (BBDR x WF)F2 大鼠隔离群体。这些将用于完成初步的交叉研究和全基因组扫描。将进行复合区间作图，结果将用于定义目标 2 中位置候选识别的 Iddm17 区间。具体目标 2 是使用标记辅助程序生成同源大鼠以精细绘制 Iddm17。在这些同类动物中，其他显性糖尿病易感基因不会分离。借助这些资源，我们将寻求鉴定 Iddm17 基因并检验以下假设：病毒感染期间 Iddm17 的反应是自身免疫性糖尿病表达的关键决定因素。 世界卫生组织：为了实现我们的目标，我们将继续在马萨诸塞大学医学院的细胞生物学家和德雷塞尔大学医学院的分子遗传学家之间进行合作安排。他们的互补活动生成了构成本应用程序基础的初步数据。 时间：我们相信我们将能够在 3 年内识别 Iddm17 基因。 底线：虽然以糖尿病大鼠的研究为中心，但该提案的重要性在于其与人类青少年糖尿病的相关性。 NIH 和 JDRF 建立了人类 1 型糖尿病遗传学联盟来识别易感基因，并建立了“年轻人糖尿病的触发因素和环境决定因素”项目。我们提出的鉴定 Iddm17 基因的工作有可能为这两项努力的目标做出重要贡献。