Endoplasmic Reticulum Thiol Redox State and Unfolded Protein Response in Aging

衰老过程中内质网硫醇氧化还原状态和未折叠蛋白反应

• 批准号: 8918824
• 负责人: Vyacheslav M Labunskyy
• 金额: $ 24.9万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918824
• 关键词: Address; Age; Aging; Aging-Related Process; Animal Model; Biology; Biology of Aging; Caenorhabditis elegans; Cell Aging; Cells; Cellular Stress; Cellular Stress Response; Chemicals; Collection; Commit; DNA Microarray Chip; Data; Development; Diabetes Mellitus; Disease; Disulfides; Dithiothreitol; Endoplasmic Reticulum; Environment; Eukaryotic Cell; Faculty; Fluorescence-Activated Cell Sorting; Functional disorder; Gene Deletion; Genes; Genetic; Genetic Engineering; Genetic Screening; Goals; Heat shock proteins; Homeostasis; Hospitals; Human; Hydrogen Peroxide; Hypoxia; Individual; Lead; Link; Longevity; Malignant Neoplasms; Measures; Mediating; Medical; Mentors; Mentorship; Metabolism; Microarray Analysis; Modification; Molecular Chaperones; Mutation; Nerve Degeneration; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phase; Play; Positioning Attribute; Protein Secretion; Proteins; Quality Control; RNA Splicing; Reporter; Research; Research Personnel; Research Training; Resistance; Role; Saccharomyces cerevisiae; Saccharomycetales; Scientist; Signal Pathway; Signal Transduction; Stress; Stress Response Signaling; Sulfhydryl Compounds; Testing; Training Programs; Translations; Tunicamycin; Up-Regulation; Woman; Yeasts; age related; aged; base; biological adaptation to stress; career; career development; cell age; cell type; chemical genetics; comparative genomics; disulfide bond; endoplasmic reticulum stress; high throughput screening; improved; in vivo; inhibitor/antagonist; insight; longevity gene; medical schools; mutant; novel; novel therapeutics; nucleotide analog; overexpression; prevent; protein aggregation; protein folding; protein misfolding; response; sensor; small molecule; stress protein; transcription factor

ENDOPLASMIC RETICULUM THIOL REDOX STATE AND UNFOLDED PROTEIN RESPONSE IN AGING My long-term goals are focused on understanding the basic mechanisms of aging and I am strongly committed to pursuing an academic career as an independent investigator. This proposal describes a comprehensive 5-year training program for my career development and transition to a tenure-track faculty position in the field of aging research. The mentored phase of the proposal will be carried out under the mentorship of Dr. Vadim Gladyshev, a well-established expert in redox biology and comparative genomics, and the co-mentorship of Dr. Gary Ruvkun, a pioneering researcher in the biology of aging, genetics and metabolism. Additionally, an advisory panel of established medical scientists with expertise in the ER unfolded protein stress response, redox signaling, and fluorescence activated cell sorting analysis consisting of Drs. Joseph Loscalzo, Gokhan Hotamisligil and Ronglih Liao will provide further scientific and career guidance. The planned career development activities will be carried out at the Brigham and Women's Hospital and Harvard Medical School, which provide an excellent research and training environment. Research plan: ER stress and protein misfolding have been shown to play an important role in aging and pathogenesis of various age-related diseases, such as diabetes, cancer and neurodegeneration. Cells adapt to accumulation of misfolded proteins in the ER by activating an evolutionary conserved protective mechanism known as the unfolded protein response (UPR). This signaling pathway restores ER homeostasis by degrading misfolded proteins, inhibiting translation, and facilitating protein folding and secretion. Although UPR dysfunction is increasingly recognized as a contributing factor to the pathophysiology of age-related diseases, the role of UPR signaling in regulating lifespan is not known. This proposal will test the hypothesis that modulating UPR signaling, either pharmacologically or genetically, can activate protective cellular stress responses and mediate lifespan extension. Our preliminary data demonstrate that constitutive up-regulation of the UPR signaling due to "mild" ER stress caused by selective inactivation of individual protein folding and maturation factors in the ER leads to increased longevity in budding yeast. We also found that extended lifespan in these ER/secretory pathway mutants is dependent on functional ER stress sensor protein, Ire1p, and is associated with ER hyperoxidation, suggesting that redox status in the ER is closely interlinked with the UPR signaling and is an important determinant of S. cerevisiae lifespan. Building upon these findings, we propose to address the following specific questions: (i) What are the mechanisms by which UPR and ER redox state regulate longevity? (ii) How protein folding capacity and redox state in the ER change with age? (iii) Can modulation of the UPR with small molecule compounds be used to improve ER stress resistance and regulate aging process?

衰老过程中内质网硫醇氧化还原态和未折叠蛋白的反应 我的长期目标是了解衰老的基本机制，并且我强烈支持 致力于以独立研究者的身份追求学术生涯。该提案描述了一个 为期 5 年的综合培训计划，帮助我的职业发展和向终身教授的过渡 在衰老研究领域的地位。该提案的指导阶段将在 Vadim Gladyshev 博士是氧化还原生物学和比较基因组学领域的知名专家， 以及衰老生物学、遗传学和遗传学领域的先驱研究员 Gary Ruvkun 博士的共同指导 代谢。此外，由具有急诊室专业知识的知名医学科学家组成的咨询小组 未折叠蛋白应激反应、氧化还原信号传导和荧光激活细胞分选分析 由博士组成。 Joseph Loscalzo、Gokhan Hotamisligil 和 Ronglih Liao 将提供进一步的科学和 职业指导。计划中的职业发展活动将在布里格姆和 妇女医院和哈佛医学院提供出色的研究和培训 环境。研究计划：内质网应激和蛋白质错误折叠已被证明发挥重要作用 衰老和各种与年龄相关的疾病的发病机制，例如糖尿病、癌症和 神经变性。细胞通过激活内质网来适应错误折叠蛋白质的积累 进化保守的保护机制称为未折叠蛋白反应（UPR）。这 信号通路通过降解错误折叠的蛋白质、抑制翻译和恢复内质网稳态 促进蛋白质折叠和分泌。尽管UPR功能障碍越来越被认为是一种 年龄相关疾病的病理生理学影响因素，UPR信号在调节中的作用 寿命未知。该提案将测试调制 UPR 信号的假设 药理学或遗传上，可以激活保护性细胞应激反应并介导寿命 扩大。我们的初步数据表明，UPR 信号的组成性上调归因于 由单个蛋白质折叠和成熟因子的选择性失活引起的“轻度”内质网应激 ER 可以延长芽殖酵母的寿命。我们还发现，这些产品的使用寿命更长 ER/分泌途径突变体依赖于功能性 ER 应激传感器蛋白 Ire1p，并且 与 ER 过度氧化相关，表明 ER 中的氧化还原状态与 UPR 信号传导是酿酒酵母寿命的重要决定因素。基于这些发现，我们 建议解决以下具体问题： (i) 普遍定期审议和普遍定期审议的机制是什么？ 氧化还原态调节寿命？ (ii) ER 中的蛋白质折叠能力和氧化还原状态如何随年龄变化？ (iii) 用小分子化合物调节 UPR 是否可用于提高 ER 应激抵抗力 并调节衰老过程？