GENETIC ANALYSIS AND CHARACTERIZATION OF IDDM GENES

胰岛素依赖型(I型)糖尿病(IDDM)是一种 年发病率在0.3%至1%之间的公共卫生问题 不同的人群。尽管进行了深入的调查，但该病的病因 IDDM仍不清楚。IDDM显然与自身免疫反应有关 对胰岛β细胞的作用。在人、小鼠和大鼠身上的研究 表明主要组织相容性复合体中的一个或多个基因 (MHC)解释了一些遗传性的疾病易感性， 而除MHC外的其他基因也参与了MHC的发病 IDDM。生物繁育(BB)大鼠被认为是最好的动物之一 发病和发病机制与人类极为相似的IDDM模型 除淋巴细胞减少外的IDDM，我们一直在描述BB大鼠的特征 从生理和基因上作为IDDM的模型。以前我们有过 证明了至少有三个基因与发育有关 几个杂交组合遗传分析对BB大鼠IDDM的影响 (在BB和非IDDM大鼠之间)：Iddm1(LYP)，它紧密地 与4号染色体上的神经肽Y(NPY)基因连锁，Iddm2连锁 20号染色体上的MHC和Fischer(F344)大鼠品系的IddM3 携带一种等位基因赋予抗性。在这次研究之后，我们出发了 BB大鼠和F344大鼠之间的新杂交。然后，我们最近有 因此，这项研究的下一阶段是 按位置克隆IddM3，并表征它们的功能和 生理角色。因此，我们提出了三个具体目标 此PPG应用程序中的项目3：1.开发同源动物 IddM3.一旦确定了BB大鼠的遗传易感性， 持续的生理特征对于病情好转是必不可少的 对这些基因的理解。实现这一目标的一种方法是 培育同源动物。在这项拨款提案中，我们将开发一个 Iddm3同源品系。我们还将培育两个Iddml同源品系 项目1.2.克隆和鉴定IddM3。自大鼠基因组计划以来 正在为位置克隆提供工具，如密集遗传图谱 和大插入文库，在大鼠中的位置克隆策略现在 很容易驯服。我们将进行同源图谱来识别人类 IddM3的同源物。3.识别其他IDDM基因 全基因组扫描策略。我们已经在2号染色体上发现了Iddm3。 我们的数据还表明，IddM3可能是一种修饰语和其他 IDDM基因可能参与了这一过程。此外，还有性别问题 与跳代效应的差异，暗示潜力 表观遗传因素的参与。我们将继续研究这些交叉 以及现在正在产生的更多动物，以提供更多 识别其他IDDM基因以及调查的统计能力 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.