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: 7729655
• 负责人: Feroz R Papa
• 金额: $ 37.08万
• 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/7729655
• 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; Upper arm; Work; 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）：许多最近的研究将2型糖尿病（T2D）的发展与内质网（ER）应激联系起来，这种疾病会在分泌途径中蛋白质折叠需求压倒性蛋白质折叠能力时发生。值得注意的是，有越来越多的证据表明，ER应力会导致葡萄糖反应性胰岛素分泌减少？ - 细胞，细胞凋亡以及一般的外周胰岛素抵抗，这是T2D的所有标志。 ER应力触发展开的蛋白质反应（UPR）途径，该途径减慢了翻译和转录上调，从而增强了ER蛋白质折叠能力的基因。如果没有通过这些输出来恢复体内平衡，则UPR会触发凋亡。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？ - 电池命运。我们的项目目标是使用介入方法在分子水平上研究这些转换。公共卫生相关性：2型糖尿病（T2D）影响1800万美国人，国家医疗保健和生产率损失每年超过1000亿美元。 T2D以补偿胰岛素抵抗的状态开始。当大约50％的产生胰岛素的胰岛胰岛中约有50％的人会发生弗兰克疾病吗？对2细胞模仿的详细理解，要合理地对T2D进行攻击。我们假设必须过度劳累的压力可能是造成T2D死亡的原因。在此提案中，我们正在使用分子和细胞方法测试此概念。