Aging and organismal proteostasis-Project 4 RM

衰老与机体蛋白质稳态-Project 4 RM

• 批准号: 10432035
• 负责人: RICHARD I MORIMOTO
• 金额: $ 41.59万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432035
• 关键词: Acute; Affect; Afferent Neurons; Aging; Animals; Autophagocytosis; Biological Models; Caenorhabditis elegans; Cells; Cellular Stress; Characteristics; Chemicals; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Development; Distal; Engineering; Ensure; Event; Exposure to; Failure; Fertility; Genetic; Germ Lines; Goals; Heat-Shock Response; Individual; Intestines; Knowledge; Longevity; Lysosomes; Modeling; Molecular; Molecular Chaperones; Mus; Muscle; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organism; Pathway interactions; Patients; Phenotype; Physiological; Property; Proteins; Proteomics; Quality Control; RNA Interference; Regulation; Reporter; Resistance; Risk; Signal Transduction; Stress; System; Techniques; Tissues; Ubiquitin; Yeasts; age effect; age related; base; biological adaptation to stress; biological systems; cell type; emerging adult; experimental study; genetic approach; inducible gene expression; multicatalytic endopeptidase complex; normal aging; polyglutamine; prevent; programs; protein aggregation; proteostasis; proteotoxicity; resilience; response; sensor; small molecule; stem cells; stress resilience; superoxide dismutase 1; synergism; tau Proteins; tau expression; tool; transcriptomics

Project 4 Summary- Morimoto Aging leads to proteostasis failure at the organismal level and is associated with the increased risk for misfolding, aggregation, and neurodegenerative disease. The emphasis of this Project is on organismal proteostasis, to understand how intertissue regulation of the proteostasis network (PN) between neurons and non-neuronal tissues of C. elegans. Our goals are to establish how communication between tissues ensures healthy proteostasis, to identify the basis for failure in quality control in aging, and how expression of Tau, SOD1, and polyglutamine causes amplification of proteotoxicity directly relevant to neurodegenerative disease. C. elegans has the advantages of transparency, detailed lineage relationships, and powerful genetic and molecular tools that are ideal to assess synthesis, folding, the ubiquitin-proteasome and autophagy lysosome pathway in tissues of wild type animals during normal aging. These results will be compared to short-and-long lived animals, and exposure to acute (heat shock) and chronic (Tau, SOD1, and polyglutamine) proteotoxic stress to identify the critical components of the PN that are essential for rapid response and protection. In C. elegans and other metazoans, the PN is regulated by cell non-autonomous control; for example, the organismal heat shock response (HSR) is regulated by sensory neurons that control induction of the HSR and properties of the PN in distal somatic tissues, moreover inducibility of the HSR declines in early adulthood by signal(s) from germ line stem cells that results in reduced tissue resilience post fecundity. The Aims are to: (1): Examine the effects of aging and proteotoxic stress on PN composition and properties. We will use proteostasis reporters (Core B) to assess and quantify folding, transport, and degradation in different tissues during development and aging, and upon exposure to physiological and proteotoxic stress, relate PN functionality to PN composition in tissues using cell type-specific transcriptomic profiling and proteomics (Cores B, C), and establish how the PN adjusts in short-and long-lived animals, (2): Examine how intertissue stress signaling in aging is affected by Tau, SOD1, and polyglutamine proteins. We will use genetic approaches to perturb the PN in neurons, muscle, intestine to identify tissue circuits and directionality of stress signaling across tissues, determine the effects of aging and expression of Tau, SOD1, and polyglutamine proteins on intertissue communication, and whether PN modulation in sending or receiving tissues can restore proteostasis against proteotoxicity, and (3): Deploy proteostasis regulators to restore organismal proteostasis in aging and neurodegeneration. With Core D, we will develop strategies for PN modulation by small molecule Proteostasis Regulators to prevent proteostasis failure during aging and proteotoxicity of Tau, SOD1, and polyglutamine. The targets will be validated using genetic approaches (RNAi and CRISPR) and proteostasis sensors (Core B). We will establish chemical strategies to reset the PN, restore stress resilience, counteract the age-dependent decline in proteostasis, and prevent proteotoxicity.

项目4总结-森本 衰老会导致机体水平上的蛋白质稳态失败，并与以下风险增加相关： 错误折叠、聚集和神经退行性疾病。该项目的重点是有机 蛋白质稳态，了解神经元和蛋白质之间的蛋白质稳态网络 (PN) 的组织间调节如何 线虫的非神经元组织。我们的目标是建立组织之间的沟通如何确保 健康的蛋白质稳态，以确定衰老质量控制失败的基础，以及 Tau 的表达如何， SOD1 和聚谷氨酰胺会导致与神经退行性疾病直接相关的蛋白毒性放大 疾病。线虫具有透明、谱系关系详细、遗传力强等优点 以及非常适合评估合成、折叠、泛素蛋白酶体和自噬的分子工具 正常衰老过程中野生型动物组织中的溶酶体途径。这些结果将与 短命和长寿动物，以及暴露于急性（热休克）和慢性（Tau、SOD1 和聚谷氨酰胺） 蛋白毒性应激可识别 PN 的关键成分，这些成分对于快速反应和 保护。在秀丽隐杆线虫和其他后生动物中，PN受到细胞非自主控制的调节；为了 例如，机体热休克反应（HSR）是由控制感应的感觉神经元调节的。 远端体细胞组织中 HSR 和 PN 的特性，此外，早期 HSR 的诱导能力下降 成年期受到生殖系干细胞信号的影响，导致生育后组织弹性降低。这 目的是： (1)：检查老化和蛋白毒性应激对 PN 成分和特性的影响。 我们将使用蛋白质稳态报告基因（核心 B）来评估和量化蛋白质的折叠、运输和降解。 不同的组织在发育和衰老过程中，以及在暴露于生理和蛋白毒性应激时， 使用细胞类型特异性转录组分析将 PN 功能与组织中的 PN 组成联系起来， 蛋白质组学（核心 B、C），并确定 PN 如何在短命和长寿动物中进行调整，(2)：检查如何 衰老过程中的组织间应激信号受到 Tau、SOD1 和聚谷氨酰胺蛋白的影响。我们将使用 扰乱神经元、肌肉、肠道中的 PN 的遗传方法可识别组织回路和方向性 跨组织的应激信号传导，确定衰老和 Tau、SOD1 和表达的影响 多聚谷氨酰胺蛋白对组织间通讯的影响，以及 PN 调节是否在发送或接收中 组织可以恢复蛋白质稳态以抵抗蛋白质毒性，并且（3）：部署蛋白质稳态调节剂以恢复 衰老和神经变性中的有机体蛋白质稳态。通过 Core D，我们将为 PN 制定策略 通过小分子蛋白质稳态调节剂进行调节，以防止衰老和衰老过程中蛋白质稳态失灵 Tau、SOD1 和聚谷氨酰胺的蛋白质毒性。将使用遗传方法（RNAi 和 CRISPR）和蛋白质稳态传感器（核心 B）。我们将制定化学策略来重置 PN， 恢复应激能力，抵消年龄依赖性的蛋白质稳态下降，并预防蛋白质毒性。