Chaperone-mediated mechanisms of cellular proteostasis

分子伴侣介导的细胞蛋白质稳态机制

• 批准号: 10620389
• 负责人: KEVIN ANTHONY MORANO
• 金额: $ 38.69万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620389
• 关键词: Alzheimer' s Disease; Amyloid; Animals; Autophagocytosis; Biochemical; Biological; Biological Models; Buffers; Cell Nucleus; Cells; Cytoplasm; Cytoprotection; Cytosol; Diabetes Mellitus; Disease; Drosophila genus; Endoplasmic Reticulum; Ensure; Equilibrium; Future; Glutathione; Goals; Growth; Health; Human; Huntington Disease; Investigation; Link; Mediating; Molecular Chaperones; Neurodegenerative Disorders; Oxidants; Oxidation-Reduction; Parkinson Disease; Pathway interactions; Proliferating; Property; Proteins; Quality Control; Reactive Oxygen Species; Research Proposals; Role; Stress; System; TXN gene; Therapeutic Intervention; Tissues; Ubiquitin; Work; Xenobiotics; Yeasts; amyloid formation; amyloid structure; arm; empowerment; experience; fly; misfolded protein; multicatalytic endopeptidase complex; novel; oxidation; oxidative damage; programs; protein aggregation; protein folding; protein misfolding; proteostasis; proteotoxicity; response; stressor; therapeutic development; transcription factor

PROJECT SUMMARY A broad range of major diseases ranging from diabetes to neurodegenerative disorders including Alzheimer's (AD), Parkinson's (PD) and Huntington's (HD) diseases have been linked to protein misfolding and aggregation. Normal protein homeostasis (proteostasis) in the cytosol and nucleus is maintained by networks of factors that promote protein folding (molecular chaperones) or clearance of terminally misfolded substrates (ubiquitin-proteasome system (UPS), autophagy). Cells grow and proliferate under the constant threat of intrinsic and extrinsic proteotoxic stressors including reactive oxygen species (ROS), exogenous oxidants and reactive electrophiles. However, the interface between proteostasis and cellular reduction-oxidation (redox) buffering pathways, namely the thioredoxin and glutathione systems, is not well understood. Our long-term goal is a comprehensive understanding of the biological roles of cytoprotective chaperones, the machinery employed to maintain redox balance and the interplay between them. In this MIRA application we define two independent themes that define our future research program. In the first line of investigation, we will examine redox modulation of cytoplasmic spatial protein quality control and degradation, empowered by our discoveries that the sequestrase Hsp42 accumulates with misfolded proteins and is required for optimal growth in redox-deficient yeast cells that lack a functional thioredoxin system. We have also uncovered a new arm of the endoplasmic reticulum-based unfolded protein response (UPR) pathway that is activated in thioredoxin-deficient cells and operates independently of the primary UPR transcription factor Hac1; we will elucidate the mechanism and biological relevance of this alternate cytoprotective system. The second broad direction will expand our studies of metazoan chaperone mechanisms with both biochemical and animal-based studies using Drosophila based on our discovery of a novel intrinsically disordered region (IDR) in fly and human Hsp110 chaperones with powerful anti-aggregation and anti-amyloid properties. The work outlined in this proposal will expand on our past successful studies of cellular redox and protein quality control networks, exploiting tractable yeast and fly model systems. These results in turn will guide future development of therapeutic interventions targeting ROS- and protein quality control-based disorders.

项目摘要 从糖尿病到神经退行性疾病等一系列重大疾病 包括阿尔茨海默病（AD）、帕金森病（PD）和亨廷顿病（HD）在内的疾病 与蛋白质的错误折叠和聚集有关。正常蛋白质稳态 细胞质和细胞核中的蛋白质代谢（蛋白质稳态）是由因子网络维持的， 促进蛋白质折叠（分子伴侣）或清除末端错误折叠 底物（泛素-蛋白酶体系统（UPS），自噬）。细胞生长和增殖 在内在和外在蛋白毒性应激源的持续威胁下， 活性氧（ROS）、外源性氧化剂和活性亲电体。 然而，蛋白质稳态和细胞还原-氧化（氧化还原） 缓冲途径，即硫氧还蛋白和谷胱甘肽系统， 明白我们的长期目标是全面了解 细胞保护分子伴侣，用于维持氧化还原平衡的机制， 它们之间的相互作用。在这个MIRA应用程序中，我们定义了两个独立的主题 决定了我们未来的研究计划在调查的第一线，我们将检查 细胞质空间蛋白质质量控制和降解的氧化还原调节， 我们发现螯合酶Hsp 42积累了错误折叠的 蛋白质，并需要在氧化还原缺陷的酵母细胞，缺乏一个最佳的增长。 功能性硫氧还蛋白系统我们还发现了一个新的内质网分支 基于网状结构的未折叠蛋白反应（UPR）途径，在 硫氧还蛋白缺陷的细胞和运作独立的主要UPR转录 因子Hac 1;我们将阐明这种替代的机制和生物学相关性 细胞保护系统第二个大方向将扩大我们对后生动物的研究 生物化学和基于动物的研究， 基于我们在果蝇中发现的一个新的内在无序区（IDR）， 和具有强大的抗聚集和抗淀粉样蛋白的人Hsp 110分子伴侣 特性.这项建议所概述的工作将在我们过去成功研究的基础上加以扩展 细胞氧化还原和蛋白质质量控制网络，利用易处理的酵母和苍蝇 模型系统这些结果反过来将指导未来的治疗发展 针对基于ROS和蛋白质质量控制的疾病的干预措施。