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Sec61 and ER Stress in Beta-cell Function and Type 2 Diabetes

β 细胞功能和 2 型糖尿病中的 Sec61 和 ER 应激

基本信息

批准号：
8270578
负责人：
Nicholas Gekakis
金额：
$ 32.57万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8270578
关键词：
Affect Age Animals Apoptosis Autopsy Beta Cell Candidate Disease Gene Cell Death Cell physiology Cells Data Defect Development Diabetes Mellitus Diabetic mouse Electron Microscopy Endoplasmic Reticulum Failure Family Functional disorder Genes Genetic Genetic Predisposition to Disease Genetic Screening Human Human Genetics Insulin Resistance Lead Literature Maps Molecular Chaperones Mus Mutant Strains Mice Mutation Nature Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pancreas Peripheral Pharmaceutical Preparations Phenotype Play Process Prospective Studies Protein Import Protein translocation Proteins Relative (related person)Role Stress Syndrome Testing Tissues Up-Regulation Yeasts abstracting cell type cytokine design diabetic endoplasmic reticulum stress genome wide association study insulin secretion mouse model mutant neonatal diabetes mellitus novel protein folding research study response transcription factor

项目摘要

Abstract In a phenotype-driven, genetic screen to identify novel genes that affect ¿-cell function, we found a mutation in Sec61a1 in a family of mice with diabetes. Sec61a1 encodes the protein conducting subunit of the endoplasmic reticulum (ER) translocation channel, which is responsible for protein import into the ER. Diabetes in Sec61a1 mutant mice is correlated with ¿-cell apoptosis and massively distended ER. The distended ER is consistent with ER stress, an accumulation of unfolded proteins within the ER. The cell mounts a response to ER stress, the unfolded protein response, which includes up regulation of protein folding chaperones (e.g. Bip), and, in the case that ER stress cannot be relieved, up regulation of the proapoptotic transcription factor Chop. Bip and Chop are both up regulated in diabetic Sec61a1 mutant animals. Thus, our hypothesis is that Sec61a1 mutation leads to ER stress, ¿-cell apoptosis, and diabetes. The experiments in this proposal are designed to test this hypothesis, to understand the mechanism by which Sec61a1 mutation leads to ER stress, and to ask if ER stress plays a role in the ¿-cell dysfunction that is part of type 2 diabetes.

抽象的在表型驱动的遗传筛选中识别影响 ¿ 细胞的新基因我们在糖尿病小鼠家族中发现了 Sec61a1 的突变。 Sec61a1 编码内质网的蛋白传导亚基 (ER) 易位通道，负责蛋白质输入内质网。 Sec61a1 突变小鼠的糖尿病与 ¿ 细胞凋亡相关 ER 严重扩张。扩张的 ER 与 ER 应力一致，内质网内未折叠蛋白的积累。细胞会做出反应内质网应激，即未折叠的蛋白质反应，包括蛋白质的上调折叠伴侣（例如 Bip），并且在 ER 应激无法缓解的情况下，促凋亡转录因子 Chop 的上调。 Bip 和 Chop 是两者在糖尿病 Sec61a1 突变动物中均上调。因此，我们的假设是 Sec61a1 突变会导致 ER 应激、细胞凋亡和糖尿病。这本提案中的实验旨在检验这一假设，以了解 Sec61a1 突变导致 ER 应激的机制，并询问 ER 是否压力在 2 型糖尿病的 ¿ 细胞功能障碍中发挥着重要作用。