Proteostasis and metabolism in brain aging

大脑衰老中的蛋白质稳态和代谢

• 批准号: 9414366
• 负责人: Heinrich Jasper
• 金额: $ 63.61万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9414366
• 关键词: Age; Aging; Aging-Related Process; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Animals; Autophagocytosis; Biochemical Process; Biochemistry; Bioinformatics; Biological Models; Brain; Carbon; Cell Maintenance; Cell Proliferation; Cell physiology; Complex; Data; Disease; Drosophila genus; Drosophila melanogaster; Energy Metabolism; Environment; Event; Exhibits; Functional disorder; Gene Mutation; Genetic; Genetic study; Geroscience; Global Change; Glucose Transporter; Glucosephosphate Dehydrogenase; Glycolysis; Goals; Head; Homeostasis; Insulin; Insulin Signaling Pathway; Intervention; Longevity; Mass Spectrum Analysis; Metabolic; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mutation; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organism; Oxidation-Reduction; Oxides; Pathway interactions; Pentosephosphate Pathway; Phosphotransferases; Physiological; Physiology; Protein Analysis; Proteins; Proteome; Proteomics; Regulation; Signal Pathway; Signal Transduction; System; Technology; Testing; Tissues; Translations; age related; aging brain; cell growth; fly; gene function; gene therapy; genetic approach; glucose uptake; improved; insight; knock-down; lipid metabolism; mTOR Signaling Pathway; metabolomics; mutant; neuronal metabolism; novel; novel therapeutic intervention; novel therapeutics; prevent; protein aggregate; protein aggregation; protein degradation; protein metabolism; proteostasis; response; sugar

PROJECT SUMMARY Age-related neurodegenerative diseases like Alzheimer’s Disease exhibit a breakdown in neuronal protein homeostasis (proteostasis). The relationship between age-related metabolic dysfunctions and protein aggregation in such diseases remains poorly understood. Elucidating the molecular basis for the age-related loss of proteostasis is expected to inspire new therapeutic approaches, not only for diseases like Alzheimer’s, but more broadly for a wide range of age-related diseases. Increasingly, this promise of “Geroscience” is being recognized as critical for extending our healthspan. Among the most productive experimental approaches in Geroscience is the use of genetically accessible model systems for the study of longevity. These models have allowed the identification of single gene mutations and of interventions that extend lifespan, highlighting the plasticity of the aging process and suggesting avenues to significantly alter its course. The cellular events impacted by such interventions and causing the lifespan extension, however, remain largely unclear. In many cases, the effect on longevity is associated with changes in proteostasis and metabolism. To understand the relationship between proteostasis and longevity in detail, however, requires an integrated approach that investigates the effects of lifespan extending perturbations on global protein homeostasis and metabolic flux in a well-defined genetic system. Here, the applicants propose such integration by combining the expertise of groups using genetic approaches (Jasper), proteomic and bioinformatic approaches (Schilling and Ghaemmaghami), and metabolomic approaches (Ramanathan) to develop models for protein and metabolic homeostasis in long-lived mutants of Drosophila. Recent technological advances in the field of mass spectrometry have enabled global analyses of protein turnover rates and metabolic flux in complex organisms. Combining these technologies with detailed analysis of lifespan-extending genetic perturbations is expected to provide transformative new insights into molecular changes required for longevity. The aims proposed by the applicants are to (i) assess age-related changes in global protein turnover and metabolic flux, (ii) determine if changes in energy metabolism downstream of the Jun-N-terminal Kinase and Insulin signaling pathways influence protein turnover, and (iii) perform genetic studies to explore the causes of aging and longevity. It is anticipated that combining the strengths of the Drosophila system with state-of-the-art proteomic and metabolomic approaches will significantly accelerate the discovery of fundamental mechanisms influencing physiology and cell function with age, providing new therapeutic avenues for age-related diseases.

项目摘要 年龄相关的神经退行性疾病（如阿尔茨海默氏病）表现出神经元蛋白的细分 稳态（蛋白质稳定）。 这种疾病的聚集仍然很少了解。 失去蛋白质的人是期望的人会激发新的治疗方法，不仅是像阿尔茨海默氏症这样的疾病， 但是，更广泛的与年龄相关的探索越来越多。 被认为对于扩展我们的健康范围至关重要。 在Geroscience中最有生产力的剥离之一是可吸引人的模型 这些模型的研究系统允许鉴定单个基因突变 延长寿命的干预措施，突出了PLOCSSSSSSSSSSSSSSS，并建议途径 大幅变化是由这种国际影响的蜂窝事件。 但是，扩展在许多卡斯中仍然不清楚。 在蛋白质和代谢中。 但是，要详细了解蛋白质的关系和寿命之间的关系，需要集成 研究寿命扩展对全球蛋白稳态和 在这里定义明确的遗传系统中的代谢通量。 使用遗传学方法（Jasper），蛋白质组学和生物信息学方法（Schilling and）的群体专业知识 Ghaemmaghami）和代谢组方法（Ramanathan）开发用于蛋白质和代谢的模型 果蝇长寿命突变体中的稳态。 质谱领域的最新技术进步已使全球蛋白质分析 复杂生物的周转率和代谢通量。 寿命扩展器的遗传扰动被曝光以提供变革性新的分子 长寿所需的变化。 全球蛋白质更新和代谢通量，（ii）确定您下游能量代谢的变化是否变化 Jun-N-N末端激酶和胰岛素信号通路会影响蛋白质周转，（III）进行遗传研究 探索衰老和寿命的原因。 预计将果蝇系统的优势与最先进的蛋白质组学和 代谢组方法将显着加速影响影响的基本机制 生理学和细胞功能随年龄的增长，为年龄相关的探索提供了新的治疗途径。