Aging and organismal proteostasis-Project 4 RM

项目4摘要-森本 衰老导致机体水平的蛋白平衡失败，并与增加的风险有关 错误折叠、聚集和神经退行性疾病。这个项目的重点是有机体 蛋白质平衡，以了解组织间调节之间的蛋白质平衡网络(PN)神经元和 线虫的非神经元组织。我们的目标是确定组织之间的交流如何确保 健康的蛋白质平衡，找出衰老过程中质量控制失败的基础，以及Tau如何表达， SOD1，多聚谷氨酰胺导致与神经退行性变直接相关的蛋白毒性放大 疾病。线虫具有透明性、详细的血统关系和强大的基因优势 和分子工具，是评估合成、折叠、泛素蛋白酶体和自噬的理想工具 野生型动物正常衰老过程中组织中的溶酶体途径。这些结果将与 短寿命和长寿命动物，以及急性(热休克)和慢性(牛磺酸、SOD1和聚谷氨酰胺)的暴露 蛋白毒性应激，以确定PN的关键成分，这些关键成分对于快速反应和 保护。在线虫和其他后生动物中，Pn由细胞非自主控制来调节； 例如，生物体热休克反应(HSR)由控制诱导的感觉神经元调节 HSR和Pn在远端体细胞组织中的特性，并且HSR的诱导性在早期下降 生殖系干细胞发出的信号导致生育后组织弹性降低的成年(S)。这个 目的是：(1)：研究衰老和蛋白毒性应激对Pn组成和性质的影响。 我们将使用蛋白质平衡报告(核心B)来评估和量化折叠、运输和降解 不同的组织在发育和老化过程中，以及在暴露于生理和蛋白毒性应激时， 使用细胞类型特定的转录转录谱和组织中的PN组成关联PN功能 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)：研究如何 衰老过程中的组织间应激信号受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PN以识别组织环路和方向性的遗传方法 跨组织应激信号的研究，确定衰老和Tau、SOD1和 多聚谷氨酰胺蛋白对组织间通讯的影响以及PN是否在发送或接收中调制 组织可以恢复蛋白平衡以对抗蛋白毒性，以及(3)：部署蛋白平衡调节剂以恢复 衰老和神经退行性变中的有机体蛋白平衡。通过核心D，我们将为PN制定策略 小分子蛋白抑制调节剂的调节作用以防止衰老和衰老过程中的蛋白稳定失效 牛磺酸、SOD1和聚谷氨酰胺的蛋白毒性。这些目标将使用遗传方法(RNAi)进行验证 和CRISPR)和蛋白质平衡传感器(核心B)。我们将建立化学策略来重置PN， 恢复应激韧性，抵消蛋白质稳定性随年龄增长的下降，并防止蛋白质毒性。

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.