Transcriptional control of proteostasis and aging

蛋白质稳态和衰老的转录控制

基本信息

批准号：
10605540
负责人：
Andrew Vaughn Samuelson
金额：
$ 26.96万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10605540
关键词：
ALS patients Acute Address Administrative Supplement Affect Age Age of Onset Aging Alzheimer&apos s Disease Applications Grants Area Autophagocytosis Brain region CRISPR/Cas technology Caenorhabditis elegans Cells Clinical Complex Deterioration Development Disease Etiology Family Future Gene Expression Genetic Genetic Transcription Genomics Goals Homeostasis Homologous Gene Human Impairment Intervention Investigation Link Longevity Mediating Metabolic Metabolic Activation Metabolic stress Modeling Molecular Molecular Chaperones Mutagenesis Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Nuclear Nutritional Organism Outcome Pathway interactions Pharmacology Phosphotransferases Physiological Process Protein Biosynthesis Protein Isoforms Protein Kinase Protein Kinase C Proteins Proteome Proteomics Regulation Reporter Research Resistance Resolution Role Signal Transduction Sirolimus Stress Sumoylation Pathway System Systems Biology Testing Tissues Training Training Programs Transcriptional Regulation Translations Work acute stress age related age related neurodegeneration base biological adaptation to stress biological systems career development cell type dietary restriction follow-up genetic manipulation healthy aging heat shock transcription factor homeodomain improved innovation insight normal aging novel parent grant polyglutamine preservation prevent protein degradation protein folding protein misfolding proteostasis proteotoxicity response stressor tau Proteins thermal stress transcription factor treatment strategy

项目摘要

Project Summary/Abstract: The mechanisms that maintain proteome folding and function (proteostasis), become ineffective during normal aging, contributing to the onset and progression of neurodegenerative protein misfolding diseases- including Alzheimer’s Disease. Proteostasis is sustained through integrated processes involving coordinated regulation of protein synthesis, folding, and degradation in response to diverse signals. We have identified the homeodomain- interacting protein kinase (HPK-1) as a key regulator of aging and proteostasis. Constitutive expression of hpk- 1, is sufficient to delay aging, preserve proteostasis, and promote stress resistance, while loss of hpk-1 impairs stress resistance, accelerating aging and the deterioration of the proteome. HPK-1 acts via the heat shock transcription factor (HSF-1), and the target of rapamycin complex 1 (TORC1). HPK-1 antagonizes sumoylation of HSF-1, presumably to repress gene expression. HPK-1 extends longevity by an additional independent mechanism: induction of autophagy via dietary restriction or TORC1 inactivation. HPK-1 expression is itself regulated by distinct mechanisms after nutritional or thermal stress, implying that HPK-1 may function as part of an integrated stress response to maintain proteostasis. Notably, we also have found that hpk-1 is required for maintaining proteostasis in C. elegans neurons, and a recent study found induced expression of a mammalian homolog in regions of the brain affected by neurodegeneration in Alzheimer’s Disease and Amyotrophic Lateral Sclerosis patients, suggesting an induced stress response. Our hypothesis is that HPK-1 prevents the age- associated decline of proteostasis by suppressing protein misfolding and stimulating protein turnover through the regulated gene expression of chaperones and autophagy, respectively. We will gain mechanistic insight into how HPK-1 regulates HSF-1 and affects aging and proteostasis through the use of proteomics and CRISPR/Cas9 targeted mutagenesis. We will apply combinations of stressors and activated HPK-1 to understand how HPK-1 functions as a part of an integrated system to maintain proteome function. We utilize genetic, genomic, and systems biology approaches to explore how dynamic regulation of the proteostatic network safeguards proper function of the proteome. In addition, we will employ tissue-specific gene manipulation to understand how this network acts across tissues. To determine the physiological consequences of hpk-1 on neuronal proteostasis and degeneration we will utilize a polyglutamine reporter and isoforms of tau to induce proteotoxicity within C. elegans neurons. Additionally, we will determine the role of Hipk1-3 loss (mammalian homologs of hpk-1) in the context of pharmacological interventions targeted to reduce proteotoxic effects of tau in mammalian neurons. With this work we will gain understanding of the role of HPK-1 during aging in the regulation of the proteostatic network, and insight into the manifestation of neurodegenerative diseases.

项目摘要/摘要：维持蛋白质组折叠和功能的机制（蛋白质量）在正常情况下变得无效衰老，有助于神经退行性蛋白质疾病的发作和pRorodegesssesset 阿尔茨海默氏病。蛋白质的合成，折叠和降解响应不同的信号。相互作用的蛋白激酶（HPK-1）作为衰老和蛋白质的关键调节剂。提供1，以延迟衰老，保留蛋白质量并促进压力抗性，而HPK-1的损失会损害耐应力，加速衰老和蛋白质组的恶化。转录因子（HSF-1）和雷帕霉素复合物1（TORC1）的靶标 HSF-1的抑制作用，HPK-1可以延长寿命机制：通过饮食限制或TORC1灭活的自噬的指示。在或热应力之后受不同机制的调节，这意味着HPK-1可能起作用综合应力响应以维持蛋白质的响应。维持秀丽隐杆线虫神经元中的蛋白质抑制作用，最近的一项研究发现哺乳动物的表达在阿尔茨海默氏病和肌萎缩性侧面受神经退行性影响影响的大脑区域的同源物硬化症患者，表明我们的应力反应是HPK-1可防止年龄通过抑制蛋白质错误折叠并刺激蛋白质流通过的蛋白质抑制剂的相关下降伴侣的常规基因表达和自噬，我们将获得机械性。 HPK-1如何调节HSF-1并通过使用蛋白质组学和 CRISPR/CAS9靶向mutajenesis。了解HPK-1如何作为保持蛋白质组函数的集成系统的功能遗传，基因组和系统生物学方法可利用蛋白抑制的动态调节蛋白质组的网络保障措施。操纵该网络如何跨组织起作用。 OFK-1在神经元蛋白质上和变性我们将利用多谷氨酰胺的Asoforts ofuu。为了在秀丽隐杆线虫神经元内诱导蛋白质毒性。（HPK-1的哺乳动物同系物）在旨在减少蛋白质毒性的药理学干预措施中 tau在哺乳动物神经元中的作用。在蛋白抑制网络的调节中，进入神经退行性疾病的表现。