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.

项目总结 从糖尿病到神经退行性疾病等一系列重大疾病 阿尔茨海默氏症(AD)、帕金森氏症(PD)和亨廷顿病(HD)等疾病 与蛋白质的错误折叠和聚集有关。正常蛋白质动态平衡 胞浆和胞核中的(蛋白稳定)是由下列因素组成的网络维持的 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，包括 活性氧物种(ROS)、外源氧化剂和活性亲电体。 然而，蛋白质平衡和细胞还原氧化(氧化还原)之间的界面 缓冲途径，即硫氧还蛋白和谷胱甘肽系统，并不是很好 明白了。我们的长期目标是全面了解生物作用 在细胞保护性伴侣中，用来维持氧化还原平衡和 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 定义了我们未来的研究计划。在一线调查中，我们将审查 氧化还原调控胞质空间蛋白的质量控制和降解， 我们发现封闭酶Hsp42以错误折叠的方式积累 蛋白质，是氧化还原缺陷型酵母细胞最佳生长所必需的 功能性硫氧还蛋白系统。我们还发现了内质网的一个新臂 基于网织的未折叠蛋白反应(UPR)途径被激活 硫氧还蛋白缺乏的细胞，独立于初级UPR转录而运作 因子Hac1；我们将阐明这种替代的机制和生物学意义 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。 生化和基于动物的研究中的伴侣机制 果蝇基于我们在果蝇中发现的一个新的固有无序区(IDR) 和具有强大的抗聚集和抗淀粉样蛋白的人Hsp110伴侣蛋白 属性。这项建议中概述的工作将在我们过去成功研究的基础上进行扩展 细胞氧化还原和蛋白质质量控制网络，利用易驯服的酵母和苍蝇 模型系统。这些结果反过来将指导治疗的未来发展 针对基于ROS和蛋白质质量控制的疾病的干预措施。