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: 8549048
• 负责人: Vyacheslav M Labunskyy
• 金额: $ 13.15万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8549048
• 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

DESCRIPTION (provided by applicant): 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?

描述（由申请人提供）：我的长期目标专注于了解衰老的基本机制，我强烈致力于从事独立研究者的学术职业。该提案描述了我的职业发展和过渡到衰老研究领域的终身教师职位的全面的5年培训计划。该提案的指导阶段将在氧化还原生物学和比较基因组学专家Vadim Gladyshev博士的指导下进行，以及Gary Ruvkun博士的同学，Gary Ruvkun博士是Aging，Aging，遗传学和代谢性生物学研究人员。此外，在ER展开的蛋白质应激反应，氧化还原信号传导和荧光激活的细胞分析分析中，成熟的医学科学家的咨询小组具有专业知识。 Joseph Loscalzo，Gokhan Hotamisligil和Ronglih Liao将提供进一步的科学和职业指导。计划的职业发展活动将在杨百翰和妇女医院和哈佛医学院进行，该医学院提供了出色的研究和培训环境。研究计划：ER应力和蛋白质错误折叠已被证明在各种与年龄有关的疾病（例如糖尿病，癌症和神经变性）的衰老和发病机理中起重要作用。细胞通过激活一种称为展开的蛋白质反应（UPR）的进化保守保护机制来适应ER中错误折叠的蛋白质的积累。该信号通路通过降解错误折叠的蛋白质，抑制翻译并促进蛋白质折叠和分泌来恢复ER稳态。尽管UPR功能障碍越来越多地被认为是与年龄相关疾病的病理生理的促成因素，但尚不清楚UPR信号在调节寿命中的作用。该提案将检验以下假设：在药理或遗传上调节UPR信号传导可以激活保护性细胞应力反应并介导寿命扩展。我们的初步数据表明，由于选择性灭活单个蛋白质折叠和ER中的成熟因子导致的“轻度” ER应激引起的构型上调，导致萌芽酵母的寿命增加。我们还发现，在这些ER/分泌途径突变体中的延长寿命取决于功能性ER应力传感器蛋白IRE1P，并且与ER高氧化有关，表明ER中的氧化还原状态与UPR信号密切相互交流，并且是塞雷维氏菌寿命的重要决定因素。在这些发现的基础上，我们建议解决以下特定问题：（i）UPR和ER氧化还原国家规范寿命的机制是什么？ （ii）ER中的蛋白质折叠能力和氧化还原状态如何随着年龄的增长而变化？ （iii）可以使用小分子化合物对UPR的调节来改善ER应力抗性和调节衰老过程？