Regulation of Peripheral Proteostasis

外周蛋白质稳态的调节

• 批准号: 9412666
• 负责人: RICHARD I MORIMOTO
• 金额: $ 297.75万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9412666
• 关键词: Acute; Address; Affect; Afferent Neurons; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Caenorhabditis elegans; Cellular Stress; Chromatin; Chronic; Communication; Disease; Ensure; Failure; Germ Lines; Health; Heat-Shock Response; Huntington Disease; Intestines; Molecular Chaperones; Muscle; Muscle Cells; Nerve Degeneration; Neurons; Parkinson Disease; Peripheral; Process; Property; Protein Conformation; Proteome; Regulation; Role; Serotonin; Signal Pathway; Signal Repression; Signal Transduction; Stem cells; Stress; Stress Response Signaling; Tissues; Toxic effect; Work; age effect; arm; misfolded protein; mutant; polyglutamine; protein aggregation; proteostasis; proteotoxicity; reproductive; response; sensor; tau Proteins; young adult

PROJECT SUMMARY This proposal is to examine the basis of intertissue signaling in the regulation of organismal proteostasis. We posit that tissue health is influenced by signals between peripheral tissues and neurons to establish an integrated proteostasis network (PN) in metazoans. This ensures that the proteome expressed by each tissue is engaged with its corresponding tissue PN for balanced synthesis, folding and function, and degradation. In addition to coordinating proteome health within each tissue, intertissue signaling affects the organismal response to proteotoxicity during aging. Our previous work provided some of the key observations to suggest a role for peripheral proteostasis in C. elegans. We showed that the organismal heat shock response (HSR) is regulated by a specific sensory neuron that communicates the cell stress signal via serotonin to the somatic tissues, that an imbalance in proteostasis within any single tissue sends a stress response signal to peripheral receiving tissues resulting in a compensatory transcellular chaperone response, and that germ line stem cells regulate the HSR in peripheral somatic tissues at reproductive maturity using a global chromatin repression signal to initiate PN failure in aging. These studies provide the basis for this proposal to understand the regulation and properties of peripheral proteostasis. We propose the following Aims: (1) To establish the functional properties of the tissue PN in neurons, body wall muscle cells, and intestine of C. elegans, (2) To identify the signaling pathways for communication between neurons, body wall muscle cells, and intestine for peripheral proteostasis, and (3) To examine how proteotoxic proteins Abeta, tau or polyQ affects peripheral proteostasis, and the effects of aging on aggregation and toxicity.

项目总结 这项建议是为了研究组织间信号在调节生物蛋白平衡中的基础。我们 假设组织健康受到外周组织和神经元之间信号的影响，以建立一个 后生动物的整合蛋白平衡网络(PN)。这确保了每个组织表达的蛋白质组 与其相应的组织PN结合，以平衡合成、折叠和功能以及降解。在……里面 除了协调每个组织内的蛋白质组健康外，组织间信号还会影响组织 在衰老过程中对蛋白质毒性的反应。我们之前的工作提供了一些关键的观察结果，以表明 线虫外周蛋白平衡的作用。我们发现，机体的热休克反应(HSR)是 由一种特定的感觉神经元调节，该神经元通过5-羟色胺将细胞应激信号传递给躯体 任何单个组织内的蛋白质平衡失衡向外周发送应激反应信号的组织 接受导致代偿性跨细胞伴侣反应的组织，以及生殖系干细胞 通过全局染色质抑制调控生殖成熟时外周体细胞组织中的HSR 老化时启动PN故障的信号。这些研究为这项提议提供了基础，以理解 外周蛋白平衡的调节和特性。我们建议的目标如下：(一)设立 线虫神经元、体壁肌肉细胞和肠道中组织PN的功能特性，(2)到 确定神经元、体壁肌肉细胞和肠道之间沟通的信号通路 外周蛋白稳定，以及(3)检测蛋白毒素蛋白Abeta、tau或PolyQ如何影响外周 蛋白质平衡，以及老化对聚集和毒性的影响。