GENETIC ANALYSIS AND CHARACTERIZATION OF IDDM GENES

胰岛素依赖型糖尿病（I型）是一种重要的糖尿病。 公共卫生问题，发病率为0.3%至1%， 不同的人群。尽管进行了深入的研究， 胰岛素依赖型糖尿病仍不清楚。胰岛素依赖型糖尿病明显涉及自身免疫反应 对抗胰腺β细胞人、小鼠和大鼠研究 表明主要组织相容性复合体中的一个或多个基因 (MHC)解释了一些遗传的疾病易感性， 除MHC外，其他基因也参与了 胰岛素依赖型糖尿病。生物育种（BB）大鼠是已知的最好的动物之一 发病和发病机制与人类非常相似的IDDM模型 除了淋巴细胞减少症，我们一直在描述BB大鼠 生理学和遗传学上作为胰岛素依赖型糖尿病的模型。以前我们有 至少有三个基因负责发育， 基于几种杂交的遗传分析， （BB和非IDDM大鼠之间）：Iddm1（Lyp），其紧密 与4号染色体上的神经肽Y（Npy）基因相连，Iddm2与 20号染色体上的MHC和Iddm3，Fischer（F344）大鼠品系 携带一个赋予抵抗力的等位基因在这项研究之后， BB大鼠和F344大鼠之间的新杂交。那么我们最近呢， 将Iddm 3定位在2号染色体上。因此，本研究的下一阶段是 克隆Iddm3的位置，并表征其功能， 生理作用。因此，我们提出三个具体目标， 本PPG应用程序中的项目3：1.发展同类动物 Iddm3.一旦BB大鼠的遗传倾向被确定， 持续的生理表征对于改善 了解这些基因。实现这一目标的一种方法是 发展同类动物。在这个项目中，我们将开发一个 Iddm 3同源系。我们还将开发两个Iddml同源系， 项目1。2.克隆并表征Iddm3。自从老鼠基因组计划 为定位克隆提供了工具，如密集遗传图谱 和大的插入文库，在大鼠中的定位克隆策略现在是 听话我们将进行同源性作图， Iddm3的同源物。3.利用基因组学方法鉴定其他Iddm基因 全基因组扫描策略。 我们已经确定了2号染色体上的Iddm3。 我们的数据还表明，Iddm 3可能是一种修饰剂， Iddm基因可能参与。此外，还有性别 与跳代效应的差异，表明潜在的 表观遗传因素的参与。我们将继续研究这些交叉 以及更多的动物， 统计能力，以确定其他Iddm基因，以及调查 表观遗传因素的参与。

Insulin-dependent (type I) diabetes mellitus (IDDM) is a significant public health problem with incidence ranging from 0.3 to 1 % in different populations. Despite intensive investigation, the etiology of IDDM remains unclear. IDDM clearly involves an autoimmune response against the pancreatic beta-cells. Studies in the human, mouse and rat indicate that a gene or genes in the major histocompatibility complex (MHC) account for some of the inherited predisposition to the disease, and that other genes besides MHC are involved in the pathogenesis of IDDM. The BioBreeding (BB) rat is known to be among the best animal models of IDDM with onset and pathogenesis closely resembling the human IDDM except for lymphopenia, and we have been characterizing the BB rat physiologically and genetically as a model for IDDM. Previously we have demonstrated that at least three genes are responsible for development of IDDM in the BB rat based on genetic analysis of several crosses (between the BB and the non-IDDM rat): Iddm1 (Lyp), which is tightly linked to the neuropeptide Y (Npy) gene on chromosome 4, Iddm2 linked to MHC on chromosome 20, and Iddm3 for which the Fischer (F344) rat strain carries an allele conferring resistance. After this study, we set out new crosses between the BB rat and the F344 rat. Then, we have recently mapped Iddm3 on chromosome 2. Therefore, next phase of this study is to clone Iddm3 by position, and to characterize their functions and physiological roles. Accordingly, we propose three specific aims for Project 3 in this PPG application: 1. Develop Congenic Animals for Iddm3. Once the genetic predisposition in the BB rat is identified, continued physiological characterization is essential to get better understanding of these genes. One way to accomplish this goal is to develop congenic animals. In this grant proposal, we will develop one Iddm3 congenic line. We will also develop two Iddml congenic lines with Project 1. 2. Clone and Characterize Iddm3. Since the Rat Genome Project is providing tools for the positional cloning, such as dense genetic map and large insert library, positional cloning strategy in the rat is now tractable. We will carry out homology mapping to identify human homologue for Iddm3. 3. Identify other Iddm genes with the Use of the Total Genome Scan Strategy. We have identified Iddm3 on chromosome 2. Our data has also suggested that Iddm3 could be a modifier and other Iddm genes could be involved in. In addition, there was gender difference with skipping-generation effect, suggesting potential involvement of epigenetic factors. We will continue to study these cross as well as more animals that are now being generated to provide more statistical power to identify other Iddm genes as well as to investigate the involvement of epigenetic factors.