Genetic Modifers of Diabetes

糖尿病的基因修饰剂

• 批准号: 7056132
• 负责人: STREAMSON C CHUA
• 金额: $ 27.56万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056132
• 关键词: carbohydrate metabolism; diabetes mellitus genetics; gene expression; genetic mapping; genetic markers; genetic susceptibility; genetically modified animals; genotype; hyperinsulinism; laboratory mouse; molecular cloning; noninsulin dependent diabetes mellitus; nucleic acid sequence; pancreatic islet function; pancreatic islets; polymerase chain reaction

The genetic basis of type 2 diabetes mellitus has been shown to be complex. This is not surprising given the large number of tissues that are engaged in regulating glucose metabolism: liver, muscle, fat, endocrine pancreas, the gut, and the brain. Alterations in numerous genes that affect pancreatic beta cell function and hepatic carbohydrate metabolism (all of the known MODY genes) can produce carbohydrate intolerance and hyperglycemia. Mutations in adipocytes can confer diabetes susceptibility, such as leptin deficiency, or diabetes resistance, as is the case in perilipin deficiency. Thus, loss of function mutations can provide both susceptibility to and protection from diabetes. Much more remains to be discovered about the complex relationships between the genome and the soma that regulate carbohydrate metabolism. To this end, we have utilized the existence of genetic modifiers of the obesity/diabetes syndrome of leptin receptor (Lepr) deficiency to identify novel diabetes genes. We have generated and characterized a novel diabetes phenotype of LEPR-null mice on the FVB strain. Obese LEPR-deficient mice of the FVB strain develop persistent hyperglycemia and concomitant hyperinsulinemia due to massive pancreatic beta cell mass expansion. This apparent resistance of the FVB mouse's beta cell to glucotoxicity is a genetically determined trait controlled by one major locus on mouse Chromosome 5 and we will provide evidence in support of this statement. Moreover, we will provide an experimental strategy to isolate and identify the genetic variants that confer resistance or susceptibility to glucotoxicity in the beta cell. We have three specific aims: 1. Identify a major locus (Modbl) that regulates the pancreatic beta cell response to hyperglycemia. 2. Define a critical genetic interval for Modbl at subcentimorgan resolution. 3. Identify the Modbl gene and the sequence variants that control beta cell responses to hyperglycemia.

2型糖尿病的遗传基础已被证明是复杂的。鉴于大量从事调节葡萄糖代谢的组织：肝脏，肌肉，脂肪，内分泌胰腺，肠道和大脑。影响胰腺β细胞功能和肝碳水化合物代谢（所有已知的Mody基因）的许多基因的改变会产生碳水化合物不耐症和高血糖。脂肪细胞中的突变可以赋予糖尿病易感性，例如瘦素缺乏症或糖尿病耐药性，就像Perilipin缺乏症一样。因此，功能突变的丧失可以提供对糖尿病的敏感性和保护性的敏感性。关于 基因组与调节碳水化合物代谢的SOMA之间的复杂关系。为此，我们利用了瘦素受体（LEPR）缺乏症的肥胖/糖尿病综合征的遗传修饰剂的存在来鉴定新型糖尿病基因。 我们已经产生并表征了fvb上LEPR无小鼠的新型糖尿病表型 拉紧。 FVB菌株的肥胖LEPR缺陷小鼠由于大量的胰腺β细胞质量扩张而导致持续性高血糖和伴随的高胰岛素血症。 FVB小鼠β细胞对糖毒性的这种明显抗性是一个遗传确定的特征，该性状由小鼠5号染色体上的一个主要基因座控制，我们将提供支持该陈述的证据。此外，我们将提供一种实验策略，以隔离和识别遗传变异物在β细胞中赋予抗葡萄毒性的耐药性或易感性。我们有三个具体的目标： 1。确定一个主要的基因座（MODBL），该基因座调节胰腺β细胞对高血糖的反应。 2。定义MODBL在亚中心分辨率下的关键遗传间隔。 3。识别控制β细胞响应对的modbl基因和序列变体 高血糖。