Aging and organismal proteostasis-Project 4 RM

衰老与机体蛋白质稳态-Project 4 RM

• 批准号: 10183117
• 负责人: RICHARD I MORIMOTO
• 金额: $ 42.41万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183117
• 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概要-森本 衰老导致生物体水平的蛋白质稳态失败，并与以下风险增加相关： 错误折叠、聚集和神经退行性疾病。该项目的重点是生物 蛋白质稳态，了解神经元之间的蛋白质稳态网络（PN）的组织间调节， C.优美的我们的目标是确定组织之间的交流如何确保 健康的蛋白质稳态，以确定在老化质量控制失败的基础上，以及如何表达Tau， SOD 1和多聚谷氨酰胺导致与神经退行性疾病直接相关的蛋白毒性放大 疾病C.秀丽线虫具有透明性、详细的谱系关系和强大的遗传多样性等优点。 和分子工具，是理想的评估合成，折叠，泛素蛋白酶体和自噬 在正常衰老期间野生型动物组织中的溶酶体途径。这些结果将与 短寿命和长寿命动物，以及暴露于急性（热休克）和慢性（Tau、SOD 1和多聚谷氨酰胺） 蛋白毒性应激，以确定快速反应所必需的PN关键组分， 保护In C.在线虫和其他后生动物中，PN由细胞非自主控制调节; 例如，生物体的热休克反应（HSR）是由感觉神经元控制的， 结果表明，HSR和PN在远侧体组织中的性质，而且HSR的诱导在早期下降， 生殖系干细胞的信号导致生殖后组织弹性降低。的 目的是：（1）：检查老化和蛋白毒性应激对PN组成和性质的影响。 我们将使用蛋白质稳态报告基因（核心B）来评估和定量蛋白质的折叠、转运和降解。 在发育和衰老过程中的不同组织，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学分析将PN功能性与组织中的PN组成相关联， 蛋白质组学（核心B，C），并确定PN如何在短寿命和长寿命动物中调节，（2）：检查如何 衰老中的组织间应激信号传导受Tau、SOD 1和多聚谷氨酰胺蛋白的影响。我们将使用 遗传方法干扰神经元、肌肉、肠中的PN，以识别组织回路和方向性 的压力信号在组织中，确定老化的影响和表达的Tau，SOD 1， 多聚谷氨酰胺蛋白对组织间通信的影响，以及PN调制在发送或接收中的作用 组织可以针对蛋白毒性恢复蛋白质稳态，以及（3）：部署蛋白质稳态调节剂以恢复 衰老和神经变性中的生物体蛋白质稳态。通过核心D，我们将为PN制定战略 通过小分子蛋白质稳态调节剂调节以防止衰老期间蛋白质稳态失败， Tau、SOD 1和聚谷氨酰胺的蛋白毒性。这些靶点将使用基因方法（RNAi）进行验证 和CRISPR）和蛋白质稳态传感器（核心B）。我们将建立化学策略来重置PN， 恢复压力恢复能力，抵消蛋白质稳态的年龄依赖性下降，并防止蛋白质毒性。