Endoplasmic Reticulum Thiol Redox State and Unfolded Protein Response in Aging

衰老过程中内质网巯基氧化还原状态与未折叠蛋白反应 我的长期目标集中在了解衰老的基本机制，我强烈 致力于追求学术生涯作为一个独立的调查员。该提案描述了一个 为我的职业发展和向终身教职的过渡提供了一个为期5年的综合培训计划 在老龄化研究领域的地位。建议的辅导阶段将在 Vadim Gladyshev博士是氧化还原生物学和比较基因组学方面的知名专家， 以及加里鲁夫昆博士的共同指导，他是衰老生物学、遗传学和 新陈代谢.此外，一个由在急诊室拥有专业知识的知名医学科学家组成的顾问小组 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Joseph Loscalzo博士、Gokhan Hotamisligil博士和Ronglih Liao博士组成，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进行， 妇女医院和哈佛医学院，这提供了一个优秀的研究和培训 环境研究计划：ER应激和蛋白质错误折叠已被证明发挥重要作用 在衰老和各种与年龄有关的疾病，如糖尿病，癌症和 神经变性细胞通过激活一种新的蛋白质来适应ER中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， 促进蛋白质折叠和分泌。尽管普遍定期审议的功能障碍越来越被认为是一个 作为与年龄相关的疾病的病理生理学的贡献因素，UPR信号在调节 寿命未知。这项提议将测试调节UPR信号传导的假设， 从基因上说，它可以激活保护性细胞应激反应， 扩展名.我们的初步数据表明，UPR信号的组成性上调，由于 "轻度"内质网应激是由选择性灭活单个蛋白质折叠和成熟因子引起的， ER导致芽殖酵母的寿命增加。我们还发现， ER/分泌途径突变体依赖于功能性ER应激传感器蛋白Ire1p， 与ER过氧化有关，表明ER中的氧化还原状态与 UPR信号转导是S.酿酒酵母寿命。基于这些发现，我们 建议解决以下具体问题：（一）普遍定期审议和紧急情况报告 氧化还原状态调节寿命？(ii)内质网中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可以用来改善ER应激抗性吗 调节衰老过程

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?