Dissecting the aging-associated decline in cellular proteostasis - Project 1

剖析与衰老相关的细胞蛋白质稳态下降 - 项目 1

基本信息

批准号：
10183114
负责人：
JUDITH FRYDMAN
金额：
$ 42.87万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
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/10183114
关键词：
Address Affect Age Aging Alzheimer&apos s Disease Amyloid beta-Protein Autophagocytosis Biogenesis Biological Assay Biological Models Caenorhabditis elegans Cell Survival Cells Complex Defect Degenerative Disorder Disease Disease model Equilibrium Functional disorder Genomics Human Huntington Disease Huntington gene Impairment Intervention Late-Onset Disorder Life Cycle Stages Link Longevity Modeling Molecular Molecular Chaperones Monitor Mus Neurodegenerative Disorders Output Parkinson Disease Pathway interactions Phase Predisposition Process Protein Biosynthesis Proteins Proteome Proteomics Quality Control Reporter Resistance Saccharomyces cerevisiae Solubility Stress System Testing Translating Translations Ubiquitin Ubiquitination Work Yeast Model System Yeasts age related aged environmental chemical experimental study improved induced pluripotent stem cell insight link protein misfolded protein mouse model multicatalytic endopeptidase complex polyglutamine polypeptide preservation prevent programs protein aggregation protein folding protein function protein misfolding proteostasis resilience ribosome profiling synergism tau Proteins

项目摘要

Project 1 – Frydman - Dissecting the aging-associated decline in cellular proteostasis Project Summary: The ability to maintain a functional proteome by preserving protein homeostasis, or proteostasis, is essential for cell viability. Yet, this ability declines during the process of aging. Such a collapse in proteostasis results in the accumulation of misfolded and aggregated proteins that are a hallmark of late-onset diseases including, most notably, a wide range of neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s Diseases. However, it remains largely unknown what cellular changes are responsible for the loss of protein homeostasis and the accumulation of damaged proteins during aging. We propose to define the mechanisms and consequences of this proteostasis decline in order to better understand what cellular interventions could improve the aging process and ameliorate age-related diseases. Proteostasis is maintained through the interplay of molecular chaperones, which are essential for protein folding and function, and quality control factors, including the ubiquitin-proteasome system and autophagy, which target misfolded proteins for elimination. Accumulating evidence suggests that the proteostasis balance is disrupted during aging. Yet, our understanding of how aging alters the interplay of proteostasis regulators is far from complete. This Project will examine several phases that regulate the life cycle of a protein, including translational fidelity, chaperone function, and misfolded protein management, to determine what cellular changes dictate the widespread proteostasis collapse associated with aging. Importantly, we will examine how the presence of aggregation-prone disease-linked proteins such as A-beta, tau and polyQ-expanded Huntingtin exon1 affect the interplay between proteostasis disfunction and aging. This will provide substantial insight into how age-dependent modulation of these processes might contribute to the decline in proteostasis, and associated decline in cell viability, that is a primary hallmark of aging and several late-onset human neurodegenerative diseases. In order to elucidate at a molecular level how aging affects the folding of newly translated proteins and the management of misfolded and stress-denatured proteins, we plan to exploit our collective expertise across a variety of models of aging to: (i) Examine how aging affects biogenesis and folding of newly made proteins and (ii) Determine how aging affects the management of misfolded and aggregation-prone proteins

项目1 - Frydman-剖析细胞蛋白质的衰老相关下降项目摘要：通过保留蛋白质稳态或蛋白质的蛋白质来维持功能蛋白质组的能力是必不可少的用于细胞活力。但是，这种能力在衰老过程中会下降。这种蛋白抑制作用的崩溃导致错误折叠和聚集的蛋白质的积累，这是晚期疾病的标志，包括，包括，最值得注意的是，包括阿尔茨海默氏症，帕金森氏症和亨廷顿的各种神经退行性疾病疾病。但是，在很大程度上仍然未知哪些细胞变化导致蛋白质丧失稳态和衰老过程中受损蛋白质受损的积累。我们建议定义机制和这种蛋白质的后果下降，以便更好地了解哪些细胞干预措施可以改善衰老过程并改善与年龄相关的疾病。通过分子伴侣的相互作用来维持蛋白质，这对于蛋白质至关重要折叠和功能以及质量控制因素，包括泛素 - 蛋白酶体系统和自噬，哪个靶向错误折叠的蛋白质以进化。积累的证据表明蛋白质的平衡在衰老期间被破坏。然而，我们对衰老如何改变蛋白质的调节剂相互作用的理解是远离完成。该项目将检查几个调节蛋白质生命周期的阶段，包括转化保真度，伴侣功能和错误折叠的蛋白质管理，以确定哪种细胞变化决定了与衰老相关的宽度蛋白质的塌陷。重要的是，我们将研究如何存在聚集的疾病连接蛋白，例如A-Beta，Tau和PolyQ扩展的亨廷顿蛋白 EXON1影响蛋白质的失功和衰老之间的相互作用。这将为您提供深入的见解这些过程的年龄依赖性调节可能有助于蛋白质的下降，以及相关细胞生存力的下降，这是衰老和几个晚期人类的主要标志神经退行性疾病。为了在分子水平上阐明衰老如何影响新翻译的蛋白质的折叠和管理错误折叠和压力定位的蛋白质，我们计划探索我们的集体专业知识衰老的多种模型：（i）检查衰老如何影响新制成的生物发生和折叠蛋白质和（ii）确定衰老如何影响错误折叠和聚集的管理蛋白质