Transcriptional control of proteostasis and aging

蛋白质稳态和衰老的转录控制

• 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
• 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' 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

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.

项目概要/摘要： 维持蛋白质组折叠和功能的机制（蛋白质稳态）在正常的细胞周期中变得无效。 衰老，导致神经退行性蛋白质错误折叠疾病的发生和进展-包括 老年痴呆症蛋白质稳态是通过涉及协调调节的整合过程来维持的， 蛋白质合成，折叠和降解，以响应不同的信号。我们已经确定了同源结构域- 相互作用蛋白激酶（HPK-1）作为衰老和蛋白质稳态的关键调节剂。hpk的组成性表达- 1，足以延缓衰老，保持蛋白质稳态，并促进抗应激能力，而hpk-1的损失损害 抗应激、加速衰老和蛋白质组的退化。HPK-1通过热休克发挥作用 转录因子（HSF-1）和雷帕霉素复合物1（TORC 1）的靶标。HPK-1拮抗SUMO化 HSF-1，可能是为了抑制基因表达。HPK-1延长寿命的额外独立 机制：通过饮食限制或TORC 1失活诱导自噬。HPK-1表达本身 在营养或热应激后由不同的机制调节，这意味着HPK-1可能作为 维持蛋白质稳态的综合应激反应值得注意的是，我们还发现，hpk-1是必需的， 维持C.最近的一项研究发现， 在阿尔茨海默病和肌萎缩侧索硬化症中受神经变性影响的脑区域中的同源物 硬化症患者，暗示了应激反应。我们的假设是HPK-1阻止了衰老- 通过抑制蛋白质错误折叠和刺激蛋白质周转， 分子伴侣和自噬的调控基因表达。我们将获得机械的洞察力， HPK-1如何调节HSF-1并通过使用蛋白质组学影响衰老和蛋白质稳态， CRISPR/Cas9靶向突变。我们将应用压力源和激活的HPK-1的组合， 了解HPK-1如何作为维持蛋白质组功能的集成系统的一部分发挥作用。我们利用 遗传学、基因组学和系统生物学方法来探索蛋白质抑制的动态调节 网络保障蛋白质组的正常功能。此外，我们将采用组织特异性基因 来了解这个网络在组织中的作用。为了确定生理后果 我们将利用多聚谷氨酰胺报告基因和tau蛋白的同种型 诱导C.线虫神经元此外，我们将确定Hipk 1 -3丢失的作用， （hpk-1的哺乳动物同源物）在靶向降低蛋白毒性的药理学干预的背景下 tau蛋白在哺乳动物神经元中的作用通过这项工作，我们将了解HPK-1在衰老过程中的作用。 在蛋白质稳定网络的调节，并洞察神经退行性疾病的表现。