Genetic Modifiers of Diabetes

描述(由申请人提供)：这项建议旨在确定导致糖尿病和糖尿病并发症易感性或抵抗力的基因变异。我们利用携带瘦素受体突变的近亲交配小鼠品系，开发了一种易于处理的遗传模型系统。瘦素受体缺陷引起的肥胖/糖尿病综合征与近交系的特定遗传构成之间的相互作用决定了糖尿病的易感性或抵抗力。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个已识别基因。 这项建议有三个目的： 1.为MODB1定义100-300 KBP的关键间隔。 2.确定产生非同义编码序列变异或C57BL/6和FVB等位基因之间表达差异的等位基因变体。 3.评价在诱导β细胞凋亡后，modb1等位基因对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.