Cytoprotection of Beta Cells Through Modulation of Ire1Alpha Function

通过调节 Ire1Alpha 功能对 Beta 细胞进行细胞保护

• 批准号: 7872760
• 负责人: Feroz R Papa
• 金额: $ 36.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7872760
• 关键词: Adenoviruses; Affect; American; Apoptosis; Apoptotic; Beta Cell; Biogenesis; Cell Death; Cell Fate Control; Cell Survival; Cell physiology; Cells; Cessation of life; Co-Immunoprecipitations; Cytoprotection; Data; Development; Disease; Drug Delivery Systems; Endoplasmic Reticulum; Event; Face; Functional disorder; Genes; Glucose; Goals; Healthcare; Homeostasis; Individual; Insulin; Insulin Resistance; Integral Membrane Protein; Islet Cell; Islets of Langerhans; Life; Link; Messenger RNA; Microarray Analysis; Molecular; Molecular Chaperones; Monitor; Non-Insulin-Dependent Diabetes Mellitus; Organism; Output; Oxidoreductase; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phosphotransferases; Physiological; Physiology; Play; Positioning Attribute; Process; Production; Productivity; Proinsulin; Proteins; RNA Splicing; Recombinants; Reporter; Resistance; Ribonucleases; Role; Signal Pathway; Signal Transduction; Stress; System; Testing; Translations; Work; arm; assault; base; cDNA Arrays; cost; diabetic; endoplasmic reticulum stress; insight; insulin secretion; islet; islet amyloid polypeptide; programs; protein folding; public health relevance; research study; response; secretory protein; tool; transcription factor

DESCRIPTION (provided by applicant): Numerous recent studies link development of type 2 diabetes (T2D) to endoplasmic reticulum (ER) stress, a condition that occurs whenever protein-folding requirements overwhelm protein-folding capacity in the secretory pathway. Notably, there is mounting evidence that ER stress contributes to diminished glucose-responsive insulin secretion in ?-cells, to ?-cell apoptosis, and to general peripheral insulin resistance, all hallmarks of T2D. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionally upregulates genes that enhance ER protein-folding capabilities. If homeostasis is not restored through these outputs, the UPR triggers apoptosis instead. We hypothesize that key component of the UPR, act as a toggling switches between homeostatic and apoptotic outputs, ultimately controlling ?-cell fate. Our project goal is to study these switches at the molecular level using interventional approaches. PUBLIC HEALTH RELEVANCE: Type 2 diabetes mellitus (T2D) affects 18 million Americans, with national healthcare and lost productivity costs exceeding $100 billion per year. T2D begins as a state of compensated insulin resistance; frank disease develops when approximately 50% of insulin-producing pancreatic islet ?-cells of affected individuals undergo cell death. A detailed understanding of how 2-cells die is necessary to rationally mount an assault on T2D. We hypothesize that the stress from having to overwork may be responsible for ?-cell death in T2D. In this proposal we are testing this concept using molecular and cellular approaches.

描述（由申请人提供）：最近的许多研究将 2 型糖尿病 (T2D) 的发展与内质网 (ER) 应激联系起来，每当蛋白质折叠需求压倒分泌途径中的蛋白质折叠能力时就会发生这种情况。值得注意的是，越来越多的证据表明，ER 应激会导致 β 细胞中葡萄糖反应性胰岛素分泌减少、β 细胞凋亡和一般外周胰岛素抵抗，这些都是 T2D 的标志。内质网应激会触发未折叠蛋白反应 (UPR) 途径，从而减慢翻译速度并在转录上上调增强内质网蛋白折叠能力的基因。如果这些输出没有恢复稳态，UPR 就会触发细胞凋亡。我们假设 UPR 的关键组成部分充当稳态和凋亡输出之间的切换开关，最终控制 β 细胞的命运。我们的项目目标是使用介入方法在分子水平上研究这些开关。公共健康相关性：2 型糖尿病 (T2D) 影响着 1800 万美国人，每年造成的国家医疗保健和生产力损失超过 1000 亿美元。 T2D 始于代偿性胰岛素抵抗状态；当受影响个体中大约 50% 的产生胰岛素的胰岛 β 细胞发生细胞死亡时，弗兰克病就会发生。详细了解 2 细胞如何死亡对于合理地攻击 T2D 是必要的。我们假设过度劳累带来的压力可能是导致 2 型糖尿病 (T2D) β 细胞死亡的原因。在这个提案中，我们正在使用分子和细胞方法测试这个概念。