Protein quality control in age-related diseases

年龄相关疾病中的蛋白质质量控​​制

• 批准号: 10601009
• 负责人: Jonathan C. Schisler
• 金额: $ 45.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601009
• 关键词: 5' -AMP-activated protein kinase; Acceleration; Active Sites; Adult; Aging; Alzheimer' s Disease; Apoptosis; Atrophic; Binding Proteins; Biochemical; Biology; Cardiovascular Diseases; Cell Culture Techniques; Cell Death; Cell model; Cell physiology; Cells; Cellular Metabolic Process; Cellular Stress; Cerebellar Ataxia; Cerebellar degeneration; Cerebellum; Code; Cognition; Complex; Defect; Degenerative Disorder; Disease; Energy Metabolism; Enzymes; Functional disorder; Genetic Diseases; Goals; Health; Heart failure; Heat-Shock Response; Human Genetics; Hypogonadism; Impaired cognition; Inflammatory; Link; Mediating; Mediator; Metabolic; Metabolic stress; Metabolism; Molecular; Molecular Chaperones; Molecular Conformation; Motor; Movement; Mus; Mutation; Nerve Degeneration; Neurologic; Neurons; Pathology; Pathway interactions; Patients; Phenotype; Phosphotransferases; Physiological; Play; Pre-Clinical Model; Predisposition; Protein Kinase Interaction; Proteins; Proteolytic Processing; Purkinje Cells; Quality Control; RIPK1 gene; Reaction; Regulation; Role; Signal Pathway; Signal Transduction; Spinocerebellar Ataxias; Stress; System; Testing; Tissues; Ubiquitin; age related; autosome; biophysical techniques; body system; clinical phenotype; disease-causing mutation; druggable target; engineered stem cells; flexibility; human disease; induced pluripotent stem cell; loss of function; member; mouse model; multicatalytic endopeptidase complex; novel; novel therapeutics; pharmacologic; pre-clinical; precision medicine; protein degradation; protein folding; protein function; proteostasis; response; selective expression; sensor; small molecule; stressor; ubiquitin ligase

ABSTRACT Protein quality control is vital for cellular function, encompassing pathways that help proteins fold and maintain structural conformations, as well as cellular systems that ultimately degrade proteins. Several degenerative diseases, including those that are accompanied by abnormal aging, are associated with altered protein quality control, highlighting the importance of protein fidelity in both health and disease. CHIP (carboxyl terminus of heat shock 70-interacting protein) is a multi- functional enzyme with distinct activities that contribute both to protein folding and protein degradation. Our lab recently identified the first human disease associated with CHIP mutations, with phenotypes that include accelerated aging, cerebellar ataxia and degeneration, cognitive dysfunction, and hypogonadism. Two known CHIP substrates, receptor- interacting protein kinase 3 (RIPK3) and AMP-activated kinase (AMPK), are regulated by either the degradative or re- folding activities of CHIP, respectively. These kinases regulate important cellular processes, necroptosis (an inflammatory form of programmed cell death) and cellular metabolism, both of which are central to the ability of cells to react to the stress that occurs with aging or in pathophysiological conditions. In this proposal, we seek to define the role of protein quality control in aging by determining how the various activities of CHIP regulate these recently identified substrates, and the mechanism that drives the sensitivity to cell stress when CHIP function is compromised. Our approach includes novel pre-clinical models of accelerated aging, cutting-edge cell models, and determining the molecular movements of CHIP when engaged with its substrate. We then ask how disease-causing mutations in CHIP mechanistically drive the molecular and cellular phenotypes associated with CHIP dysfunction. Finally, we will use our preclinical models to determine how aging and disease pathologies are altered when necroptosis is inhibited pharmacologically, or when CHIP function is restored genetically. The ultimate goal of these studies is to identify druggable targets of CHIP-regulated signaling pathways that impact age-dependent progression of degenerative conditions.

摘要 蛋白质质量控制对于细胞功能至关重要，包括帮助蛋白质折叠和维持结构的途径 构象，以及最终降解蛋白质的细胞系统。几种退行性疾病，包括 伴随着不正常的衰老，与蛋白质质量控制的改变有关，突出了 在健康和疾病中的蛋白质保真度。CHIP（carboxyterminal of heat shock 70-interacting protein）是一种多功能的热休克蛋白。 对蛋白质折叠和蛋白质降解都有贡献的具有不同活性的功能酶。我们的实验室最近 确定了第一个与CHIP突变相关的人类疾病，其表型包括加速老化， 小脑共济失调和变性、认知功能障碍和性腺功能减退。两种已知的CHIP底物，受体- 相互作用蛋白激酶3（RIPK 3）和AMP激活的激酶（AMPK）受降解或再降解的调节。 CHIP的折叠活性。这些激酶调节重要的细胞过程，坏死性凋亡（炎性细胞凋亡）， 程序性细胞死亡的形式）和细胞代谢，这两者都是细胞反应的能力的核心。 在衰老或病理生理条件下发生的压力。在这个建议中，我们试图定义蛋白质的作用， 通过确定CHIP的各种活动如何调节这些最近发现的 底物，以及当CHIP功能受损时驱动对细胞应力敏感性的机制。我们 方法包括加速老化的新型临床前模型，尖端细胞模型，以及确定分子水平。 当与其基底接合时，CHIP的运动。然后，我们询问CHIP中的致病突变如何 在某些实施方案中，CHIP基因可能在机制上驱动与CHIP功能障碍相关的分子和细胞表型。最后，我们将使用 临床前模型，以确定当坏死性凋亡被抑制时，衰老和疾病病理学如何改变 或者当CHIP功能在基因上恢复时。这些研究的最终目的是确定 CHIP调节的信号通路的可药物靶点影响退行性变的年龄依赖性进展 条件