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，对个人和社会来说都是非常昂贵的。长期目标是揭示BB大鼠自发性T1D发育的机制，该机制是人类疾病的模型。在此程序项目中，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。染色体20（IDDM1）上的主要组织相容性复合物（MHC），染色体4（IDDM2LLYP）上的淋巴细胞减少IAN5突变和两个抗糖尿病基因座从 F344老鼠； IDDM3在2号染色体上，染色体15染色体上的第四个因素（IDDM19）。我们在识别LYP及其转基因救援的IAN5突变以及两个电阻基因座的映射方面取得了重大进展。我们在项目1中的主要目标是研究Ian Gene家族如何赋予淋巴细胞减少症和T1D的风险。对于续约，我们以我们最近的成功为基础，并添加了新的策略，以利用 老鼠，老鼠和人类基因组计划。具体而言，我们提出的三个特定目的是测试假设，即1）新发现的抗凋亡免疫相关核苷酸（IAN）蛋白控制淋巴细胞减少症和T1D年龄依赖性的发作，或者是遗传因子的遗传因子，最终是Iltream ness the Geners neced and chendere， IDDM3和IDDM19是BBDR大鼠与MHC和Ian基因家族相互作用以诱导T1D的敏感因素。通过与项目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（到目前为止的7/11成员），它们的坐标表达和表达和表达 和目标胰岛β细胞。我们将使用新开发的先天性BBF系，这是淋巴细胞减少DR。（lypllyp）大鼠，由于渗入了23 MB糖尿病的F344基因组片段，因此不会产生T1D。我们将与项目2一起研究转基因大鼠和小鼠中关键IAN基因的功能，以及项目3，我们将开发先天性IDDM3和染色体15（IDDM19）DR。（Lypllyp）大鼠研究200多个候选糖尿病基因的表达，以F344 Elleles的抗性为F344 Elleles。在这四种不同的染色体上鉴定遗传因素应该使能够确定控制BB大鼠自发T1D发育的最终公共途径。由于这些基因座中的某些对人T1D也很重要，因此阐明了自发BB大鼠T1D的分子机制，可以鉴定出用于预防或治愈T1D的新型靶标。