Dissecting Type 1 Diabetes Genes

剖析 1 型糖尿病基因

• 批准号: 6990062
• 负责人: AKE LERNMARK
• 金额: $ 10.64万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6990062
• 关键词: diabetes mellitus genetics; disease /disorder model; gene deletion mutation; genetic mapping; genetic susceptibility; insulin dependent diabetes mellitus; laboratory mouse; laboratory rat; lymphopenia; model design /development; molecular cloning; molecular genetics; molecular pathology

Type 1 diabetes (T1D) is the most common chronic disease in children and is very costly to both the individual and society. The long-term objective is to uncover the mechanisms of spontaneous T1D development in the BB rat that serves as a model of the human disease. In this program project we use molecular genetics tools to dissect the loci associated with BB rat diabetes; the major histocompatibility complex (MHC) on chromosome 20 (Iddm1), the lymphopenia-inducing Ian5 mutation on chromosome 4 (Iddm2llyp) and two diabetes resistance loci inherited from F344 rats; Iddm3 on chromosome 2, and a fourth factor (Iddm19) on chromosome 15. We have made substantial progress in identifying the Ian5 mutation for lyp and its transgenic rescue as well as the mapping of the two resistance loci. Our primary goal in Project 1 is to study how the Ian gene family confers risk for lymphopenia and T1D. For the renewal, we build on our recent success and have added new strategies that take advantage of the progress made in the rat, mouse and human genome projects. Specifically, we propose in three specific aims to test the hypotheses that 1) the coordinate expression of the newly discovered family of anti-apoptopic Immune Associated Nucleotide (Ian) proteins controls lymphopenia and age-dependent onset of T1D, or alternatively that 2) a genetic factor(s) up-stream of the Ian family of genes is linked specifically to T1D development and, finally that 3) Iddm3 and Iddm19 are susceptibility factors in the BBDR rat interacting with MHC and the Ian family of genes to induce T1D. In collaboration with projects 2 and 3, research designs and methods for testing these hypotheses will include the complete characterization of the entire family of Ian genes (7/11 members characterized so far), their coordinate expression and expression in effector and target islet beta cells. We will use our newly developed congenic BBF line, which is a lymphopenic DR.(lypllyp) rat that does not develop T1D due to the introgression of a 23 Mb diabetes-resistant F344 genomic fragment up-stream of the Ian5 mutation. Together with project 2, we will study the function of critical Ian genes in transgenic rats and mice and with Project 3, we will develop congenic Iddm3 and chromosome 15 (Iddm19) DR.(lypllyp) rats to study the expression of more than 200 candidate genes conferring diabetes resistance as F344 alleles. The identification of genetic factors on these four different chromosomes should make it possible to identify the final common pathway(s) that control spontaneous T1D development in the BB rat. As some of these loci are also important to human T1D, elucidation of molecular mechanisms that govern spontaneous BB rat T1D may allow the identification of novel targets for therapeutic interventions to prevent or cure T1D.

1 型糖尿病 (T1D) 是儿童中最常见的慢性疾病，对个人和社会来说代价都非常高昂。长期目标是揭示作为人类疾病模型的 BB 大鼠自发发生 T1D 的机制。在这个项目中，我们使用分子遗传学工具来剖析与 BB 大鼠糖尿病相关的基因座； 20 号染色体 (Iddm1) 上的主要组织相容性复合体 (MHC)、4 号染色体上诱导淋巴细胞减少的 Ian5 突变 (Iddm2llyp) 以及遗传自 F344大鼠； Iddm3 位于 2 号染色体上，第四个因子 (Iddm19) 位于 15 号染色体上。我们在鉴定 lyp 的 Ian5 突变及其转基因拯救以及两个抗性位点的定位方面取得了实质性进展。我们项目 1 的主要目标是研究 Ian 基因家族如何赋予淋巴细胞减少症和 T1D 风险。对于更新，我们以最近的成功为基础，并添加了新的战略，以利用所取得的进展 大鼠、小鼠和人类基因组计划。具体来说，我们提出了三个具体目标来检验以下假设：1) 新发现的抗凋亡免疫相关核苷酸 (Ian) 蛋白家族的协调表达控制淋巴细胞减少和年龄依赖性 T1D 发病，或者 2) Ian 基因家族上游的遗传因素与 T1D 的发展特别相关，最后，3) Iddm3 和 Iddm19 是 T1D 的易感因素。 BBDR 大鼠与 MHC 和 Ian 基因家族相互作用诱导 T1D。与项目 2 和 3 合作，测试这些假设的研究设计和方法将包括整个 Ian 基因家族的完整表征（迄今为止已表征 7/11 个成员）、它们的坐标表达和效应子表达 和目标胰岛β细胞。我们将使用我们新开发的同源 BBF 系，这是一种淋巴细胞减少的 DR.(lyplyp) 大鼠，由于 Ian5 突变上游 23 Mb 抗糖尿病 F344 基因组片段的渗入，该大鼠不会发展为 T1D。与项目 2 一起，我们将研究转基因大鼠和小鼠中关键 Ian 基因的功能；与项目 3 一起，我们将开发同源 Iddm3 和 15 号染色体 (Iddm19) DR.(lyplyp) 大鼠，以研究 200 多种候选基因的表达赋予糖尿病抗性的基因为 F344 等位基因。对这四种不同染色体上遗传因素的鉴定应该能够确定控制 BB 大鼠自发 T1D 发展的最终共同途径。由于其中一些位点对人类 T1D 也很重要，因此阐明控制自发性 BB 大鼠 T1D 的分子机制可能有助于确定预防或治愈 T1D 治疗干预的新靶点。