The Role of Sorcs1 and Sortilin in Diabetes Susceptibility

Sorcs1 和 Sortilin 在糖尿病易感性中的作用

基本信息

批准号：
9322473
负责人：
Alan D Attie
金额：
$ 34.43万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9322473
关键词：
Affect Alleles Amish Apolipoproteins B BTBR Mouse Beta Cell Binding Cell physiology Cholesterol Code Complications of Diabetes Mellitus Defect Development Diabetes Mellitus Epidemic Generations Genes Genetic Genetic study Hepatocyte Human Impairment Individual Insulin Insulin Resistance Knockout Mice LDL Cholesterol Lipoproteins Ligand Binding Lysosomes Mediating Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Pathway interactions Peptide Hydrolases Phenotype Physiologic pulse Play Population Predisposition Production Proteins Role Site Structure of beta Cell of islet Susceptibility Gene Work base experimental study gene cloning genetic variant genome wide association study hypercholesterolemia insight insulin granule insulin secretion loss of function mutant novel novel therapeutic intervention overexpression positional cloning public health relevance sortilin trafficking

项目摘要

DESCRIPTION (provided by applicant): We are in the midst of an unprecedented obesity epidemic, which is causing an epidemic of type 2 diabetes (T2D). Obesity causes insulin resistance, resulting in an increased demand for insulin from pancreatic ß-cells. Genetic factors play a critical role in determining whether or not the ß-cells are capable of responding to the increased demand for insulin. In individuals where this insulin demand is not met, diabetes results and likely reflects some aspect of ß-cell impairment (development, proliferation, survival or insulin secretion). We positionally cloned Sorcs1, a gene that contributes to obesity-induced T2D. SORCS1 is associated with T2D and diabetes complications in humans. We derived Sorcs1 knockout (KO) mice and when obese, they develop diabetes. Pancreatic ß-cells from obese Sorcs1 KO mice have a severe deficiency in insulin granules, due to a dramatic increase in the post-translational degradation of insulin. We have shown that Sortilin, a protein related to Sorcs1, which is known to target proteins to the lysosome for degradation, binds to insulin. The pro-domain of Sorcs1 also binds to Sortilin and inhibits its activity. Our preliminary studies show that overexpression of Sortilin in ß-cells, in contrast to ß-cells overexpressing Sorcs1, decreases cellular insulin content. We hypothesize that Sorcs1 inhibits the ability of Sortilin to promote insulin degradation. The proposed studies will elucidate the role of Sorcs1 and Sortilin in determining the intracellular fate of insulin. We have identified two coding SNPs in human Sortilin (SORT1); one associated with reduced insulin levels and the other with elevated cholesterol. We will characterize these SNPs in SORT1 to understand their association with these distinct phenotypes. We will evaluate an allelic variant in mouse Sorcs1 that is associated with reduced insulin. Our proposed studies will elucidate a newly identified branch point that determines whether insulin is packaged in insulin granules, or is diverted towards degradation. We will characterize mutations in Sortilin and Sorcs1 that are associated with decreased insulin in humans and in mice. Insights from our work may provide clues to the development of novel therapeutic approaches aimed at preserving the insulin reserve of pancreatic ß-cells.

描述（由申请人提供）：我们正处于前所未有的肥胖流行之中，这是一种 2 型糖尿病 (T2D) 的流行。肥胖会导致胰岛素抵抗，从而导致胰腺 β 细胞对胰岛素的需求增加。遗传因素在决定 β 细胞是否能够对胰岛素需求增加做出反应方面发挥着关键作用，在胰岛素需求未得到满足的个体中，糖尿病的结果可能反映了 β 细胞的某些方面。损伤（发育、增殖、生存我们定位克隆了 Sorcs1，这是一种导致肥胖引起的 T2D 的基因，该基因与人类的 T2D 和糖尿病并发症有关，当肥胖时，它们会患上糖尿病。我们已经证明，由于胰岛素翻译后降解的急剧增加，来自肥胖 Sorcs1 KO 小鼠的细胞严重缺乏胰岛素颗粒。分拣蛋白（Sortilin），一种与 Sorcs1 已知将蛋白质靶向溶酶体进行降解，它与胰岛素结合。我们的初步研究表明，Sorcs1 的前结构域也与 Sortilin 结合并抑制其活性。与过度表达 Sorcs1 的 β 细胞相比，Sortilin 的过度表达会降低细胞胰岛素含量。我们发现 Sorcs1 会抑制 Sortilin 促进胰岛素降解的能力。拟议的研究将阐明 Sorcs1 和 Sortilin 在决定中的作用。我们在人分拣蛋白 (SORT1) 中发现了两种编码 SNP；一种与胰岛素水平降低相关，另一种与胰岛素水平升高相关。我们将表征 SORT1 中的这些 SNP，以了解它们与这些不同表型的关联。我们将评估与胰岛素减少相关的小鼠 Sorcs1 中的等位基因变异。我们将描述与人类和小鼠胰岛素减少相关的 Sortilin 和 Sorcs1 的突变，或者转向降解。旨在保护胰腺β细胞的胰岛素储备的方法。