Genetic Modifiers of Diabetes

描述（由申请人提供）：本提案旨在鉴定导致糖尿病和糖尿病并发症易感性或耐药性的遗传变异。我们已经开发了一个易于处理的遗传模型系统，使用携带瘦素受体突变的近交系小鼠品系。由瘦素受体缺乏引起的肥胖/糖尿病综合征与近交系的特定遗传组成之间的相互作用决定了糖尿病的易感性或抵抗性。对小鼠基因组特定染色体区域的遗传选择已经确定了小鼠5号染色体上负责糖尿病易感性的区域。该区域已减少到1500万个碱基对区域，包含约200个已识别的基因。 这项建议有三个目标： 1.为Modb 1定义100-300 kbp的临界区间。 2.鉴定在C57 BL/6和FVB等位基因之间产生非同义编码序列变体或表达差异的等位基因变体。 3.评价Modb 1等位基因对诱导β细胞凋亡后β细胞再生/增殖的影响。

DESCRIPTION (provided by applicant): This proposal aims to identify genetic variants that underlie susceptibility or resistance to developing diabetes and diabetic complications. We have developed a tractable genetic model system using inbred mouse strains carrying a mutation of the leptin receptor. The interaction between the obesity/diabetes syndrome caused by the leptin receptor deficiency and the specific genetic constitution of the inbred strain determines diabetes susceptibility or resistance. Genetic selection of specific chromosomal regions of the mouse genome has identified regions on mouse Chromosome 5 that is responsible for diabetes susceptibility. The region has been reduced to a 15 million base pair region containing ~200 identified genes. This proposal has three aims: 1. Define a critical interval of 100-300 kbp for Modb1. 2. Identify allelic variants that produce nonsynonymous coding sequence variants or expression differences between the C57BL/6 and FVB alleles. 3. Evaluate the impact of Modb1 alleles on beta cell regeneration/proliferation after induction of beta cell apoptosis.