Genetic Mapping / Beta-cell Decomposition in Type 2 Diabetes

描述（由申请人提供）：2型糖尿病包括胰岛素抵抗，并伴有胰腺β细胞无法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，但一个人可能会有严重的胰岛素抵抗，而不会患上糖尿病。因此，β细胞衰竭或β细胞失代偿是2型糖尿病的基本特征。该项目的目的是确定与2型糖尿病β细胞失代偿相关的糖尿病易感性的遗传修饰因子。该方法是将遗传学与基因阵列技术相结合。我们将绘制mRNA丰度作为2型糖尿病等位基因分离动物群体的数量性状。我们已经证明BTBR-ob/ob小鼠，与C57BLI6-ob/ob小鼠形成鲜明对比，会发生严重的糖尿病。我们已经证明，由这两种菌株产生的F2小鼠分离出糖尿病易感等位基因。在本研究中，我们建议产生（C57BL/6 × BTBR）-ob/ob F2群体。我们将从它们的胰岛中分离RNA，并使用微阵列技术定量mRNA丰度。mRNA值（基因表达性状）将被用作基因定位的表型。利用降维方法（聚类和主成分），基因表达性状将转化为超表型，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定位。

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.