Protein quality control in age-related diseases

年龄相关疾病中的蛋白质质量控制

基本信息

批准号：
10802465
负责人：
Jonathan C. Schisler
金额：
$ 7.02万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10802465
关键词：
5&apos -AMP-activated protein kinase Acceleration Active Sites Adult Aging Alzheimer&apos 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

项目摘要

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.

抽象的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并保持结构的途径构象以及最终降解蛋白质的细胞系统。几种退化性疾病，包括伴随着异常衰老的，与蛋白质质量控制的改变有关，强调了重要性健康和疾病中的蛋白质保真度。芯片（热休克的羧基末端70相互作用蛋白）是多种功能性酶具有不同的活性，既有助于蛋白质折叠和蛋白质降解。我们最近的实验室确定了与芯片突变相关的第一种人类疾病，其表型包括加速衰老，小脑共济失调和变性，认知功能障碍和性腺功能不全。两个已知的芯片底物，受体 - 相互作用的蛋白激酶3（RIPK3）和AMP激活的激酶（AMPK）受降解或重新调节芯片的折叠活动。这些激酶调节重要的细胞过程，坏死性（炎症程序性细胞死亡的形式和细胞代谢，这两者都是细胞反应能力的核心在衰老或病理生理状况下发生的压力。在此提案中，我们试图定义蛋白质的作用通过确定芯片的各种活动如何调节这些最近确定的质量控制底物以及当芯片功能受到损害时驱动细胞应激敏感性的机制。我们的方法包括新型的加速衰老，尖端细胞模型的临床前模型，并确定分子芯片与基质互动时的动作。然后，我们询问芯片中引起疾病的突变机械上驱动与芯片功能障碍相关的分子和细胞表型。最后，我们将使用我们的临床前模型，以确定抑制坏死性时衰老和疾病病理的改变在药理上，或何时恢复遗传芯片功能。这些研究的最终目标是确定芯片调节的信号通路的可药物目标，影响年龄依赖性退化的进展状况。