Chaperone-mediated mechanisms of cellular proteostasis

分子伴侣介导的细胞蛋白质稳态机制

基本信息

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
项目类别：
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&apos 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

项目摘要

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的广泛主要疾病包括阿尔茨海默氏症（AD），帕金森氏症（PD）和亨廷顿（HD）疾病在内的疾病与蛋白质错误折叠和聚集有关。正常蛋白质稳态（proteostasis）在细胞质和细胞核中的（蛋白抑制作用）是由因素网络维持的促进蛋白质折叠（分子伴侣）或终止错误折叠的清除率底物（泛素 - 蛋白酶体系统（UPS），自噬）。细胞生长和增殖在固有和外部蛋白质毒性应激源的持续威胁下活性氧（ROS），外源氧化剂和反应性电力。然而，蛋白质量和细胞还原氧化（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，不是很好理解。我们的长期目标是对生物学角色的全面理解在细胞保护伴侣的伴侣中，用于维持氧化还原平衡和他们之间的相互作用。在此MIRA应用中，我们定义了两个独立主题这定义了我们未来的研究计划。在第一行调查中，我们将检查氧化还原调节细胞质空间蛋白质质量控制和降解，我们的发现，隔离酶HSP42累积了不折叠的能力蛋白质是缺乏氧化还原的酵母细胞最佳生长所必需的功能性硫氧还蛋白系统。我们还发现了内质的新臂基于网状的展开的蛋白质反应（UPR）途径，该途径被激活硫氧还蛋白缺陷型细胞，并独立于主要UPR转录因子HAC1;我们将阐明该替代方案的机制和生物学相关性细胞保护系统。第二个宽方向将扩大我们对后生动物的研究使用生化和基于动物的研究的伴侣机制使用果蝇基于我们发现了苍蝇中新型内在无序区域（IDR）的发现和人类HSP110伴侣，具有强大的抗聚集和抗淀粉样蛋白特性。该提案中概述的工作将扩大我们过去的成功研究细胞氧化还原和蛋白质质量控制网络，利用可拖动的酵母并飞行模型系统。这些结果反过来指导未来的治疗发展针对ROS和蛋白质质量控制疾病的干预措施。