Genetic Mapping / Beta-cell Decomposition in Type 2 Diabetes

描述(申请人提供)：2型糖尿病包括胰岛素抵抗和胰岛β细胞不能补偿增加的胰岛素需求。虽然胰岛素抵抗是2型糖尿病的一个特征，但一个人可以在不发展为糖尿病的情况下出现严重的胰岛素抵抗。因此，β细胞衰竭或β细胞失代偿是2型糖尿病的一个基本特征。该项目的目标是确定与2型糖尿病中的β细胞失代偿相关的糖尿病易感性的遗传修饰因素。方法是将遗传学与基因阵列技术相结合。我们将在分离2型糖尿病等位基因的动物群体中，将信使核糖核酸丰度定位为数量性状。我们已经证明，BTBR-ob/ob小鼠与C57BLI6-ob/ob小鼠形成鲜明对比，患上严重糖尿病。我们已经证明，由这两个菌株产生的F2小鼠分离了糖尿病易感等位基因。在目前的研究中，我们建议产生(C57BL/6 x BTBR)-ob/ob F2群体。我们将从它们的胰岛中提取RNA，并使用微阵列技术来定量检测mRNA的丰度。MRNA值(基因表达性状)将作为基因定位的表型。使用降维方法(聚类法和主成分法)，基因表达特征将被转化为表型，以便对2型糖尿病中功能失调并导致β细胞失代偿的网络进行遗传作图。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus involves insulin resistance combined with a failure of pancreatic beta-cells to compensate for the increased insulin demand. Although insulin resistance is a feature of type 2 diabetes, a person can be severely insulin resistant without ever developing diabetes. Therefore, beta-cell failure, or beta-cell decompensation, is an essential feature of type 2 diabetes. The objective of this project is to identify genetic modifiers of diabetes susceptibility that are associated with beta-cell decompensation in type 2 diabetes. The approach is to combine genetics with gene array technology. We shall map mRNA abundance as a quantitative trait in a population of animals segregating for type 2 diabetes mellitus alleles. We have shown that BTBR-ob/ob mice, in stark contrast to C57BLI6-ob/ob mice, develop severe diabetes. We have shown that F2 mice generated from these two strains segregate diabetes susceptibility alleles. In the present studies, we propose to generate a (C57BL/6 x BTBR)-ob/ob F2 population. We will isolate RNA from their pancreatic islets and quantitate mRNA abundance using microarray technology. The mRNA values (gene expression traits) will be used as phenotypes for gene mapping. Using dimension reduction approaches (clustering and principal components), the gene expression traits will be transformed into superphenotypes in order to genetically map networks that are dysfunctional in type 2 diabetes mellitus and result in beta-cell decompensation.