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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 -解剖与衰老相关的细胞蛋白酶抑制下降