Illuminating Lysosomal Dysfunction in Aging and Alzheimer's Disease (AD)

阐明衰老和阿尔茨海默病 (AD) 中的溶酶体功能障碍

• 批准号: 10723110
• 负责人: Courtney E Lane-Donovan
• 金额: $ 17.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723110
• 关键词: Academic skills; Acidity; Affect; Age; Aging; Alkalinization; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer' s disease therapy; Area; Astrocytes; Automobile Driving; Autophagocytosis; Brain; Brain region; Caenorhabditis elegans; California; Cathepsins; Cell Separation; Cells; Cellular biology; Characteristics; Clinical; DNA Sequence Alteration; Data; Development; Disease; Disease susceptibility; Failure; Functional disorder; Future; Genes; Genetic Transcription; Goals; Grant; Human; Image; Immunohistochemistry; Impairment; Individual; Invertebrates; J20 mouse; Knowledge; Libraries; Lysosomes; Mammals; Memory; Mentors; Microglia; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurology; Neurons; Onset of illness; Outcome; Pathogenesis; Pathology; Patients; Peptide Hydrolases; Phenotype; Physicians; Predisposition; Program Development; Proteins; Psychiatry; Reporter; Reporting; Research; Research Personnel; Role; Running; Saccharomyces cerevisiae; San Francisco; Scientist; Stress; Testing; Therapeutic; Tissue Sample; Tissues; Training; Universities; Variant; Work; Yeasts; abeta accumulation; age effect; age related; aged; aging brain; brain cell; brain tissue; career; career development; cell type; disease prognosis; effective therapy; experience; experimental study; genetic risk factor; in vitro activity; in vivo; misfolded protein; mouse model; multicatalytic endopeptidase complex; neuroprotection; new therapeutic target; novel; particle; protein aggregation; protein degradation; protein expression; proteostasis; regional difference; sensor; skills; spatiotemporal; targeted treatment; therapeutic development; tool; transcriptomics

Project Summary/Abstract This proposal presents a five-year research career development program on the study of lysosomal pH and function in aging and disease to expand our understanding of the mechanisms by which aging contributes to neurodegenerative diseases, like Alzheimer’s disease (AD). The candidate, Dr. Courtney Lane-Donovan, is currently a Clinical Fellow in Neurology at the University of California, San Francisco, in the division of Memory and Aging. The outlined proposal builds on Dr. Lane-Donovan’s previous research experience in mouse models of AD to gain new domains of expertise represented by her mentor team of primary mentor Dr. Aimee Kao and co-mentor Dr. Anna Molofsky of the departments of neurology and psychiatry, respectively, at UCSF. The proposed experiments, didactic work, and training in academic skills will provide Dr. Lane-Donovan with a unique skillset that will enable her transition to independence as a physician scientist leader in the field of aging and neurodegenerative diseases. As our nation ages, the burden of the aging-related neurodegenerative diseases has increased substantially. How aging promotes protein aggregation in certain brain regions – and more importantly, how to reverse the effect – remains unknown. Protein aggregates can accumulate when protein degradation by proteases in the lysosome is impaired, and several genetic risk factors for AD encode proteins involved in endolysosomal function and autophagy. Lysosomal proteases function optimally at an acidic pH, and data from invertebrate models suggest that age and stress cause lysosomes to lose their acidity, resulting in impaired function; however, the relevance of these findings to human aging and disease is unclear. Regional variation in lysosomal protease activity may contribute to the selective vulnerability of certain brain regions to the accumulation of protein aggregates; however, regional lysosomal function is not fully characterized and thereby poorly understood. Together, this suggests a tantalizing hypothesis - regional variability of lysosomal protease expression leaves certain neurons more vulnerable to the lysosomal dysfunction caused by lysosomal alkalinization with age. To test this hypothesis, Aim 1 utilizes the novel lysosomal pH reporter, FIRE-pHLy (Fluorescent Indicator Reporting pH of the Lysosome) to delineate the effect of aging and amyloid beta accumulation on lysosomal pH. Aim 2 will determine regional changes in lysosomal protease activity and expression in the aging brain by combining lysosome isolations, immunohistochemistry, and spatial transcriptomics. The data generated by this study can be used to propose new models of lysosomal dysfunction in aging and disease and identify new therapeutic targets for neuroprotection in neurodegenerative disease.

项目摘要/摘要 本提案提出了一项为期五年的溶酶体研究职业发展计划。 PH值及其在衰老和疾病中的作用扩大了我们对衰老机制的理解 导致神经退行性疾病，如阿尔茨海默病(AD)。候选人考特尼博士 Lane-Donovan目前是加州大学旧金山分校神经病学的临床研究员 记忆与衰老的分野。概述的提案建立在莱恩-多诺万博士之前的研究基础上 在AD小鼠模型方面的经验，以获得由她的导师团队代表的新的专业领域 神经内科的初级导师高艾梅博士和共同导师安娜·莫洛夫斯基博士 加州大学旧金山分校的精神病学专业。建议的实验、教学工作和学术培训 Skills将为Lane-Donovan博士提供独特的技能，使她能够过渡到独立 作为衰老和神经退行性疾病领域的内科科学家领导者。 随着我们国家的老龄化，与衰老相关的神经退行性疾病的负担也增加了 基本上是这样的。衰老如何促进特定大脑区域的蛋白质聚集--更重要的是， 如何逆转这一效应--目前尚不清楚。蛋白质聚集物可以在蛋白质 溶酶体中的蛋白酶降解受到损害，AD的几个遗传危险因素编码 参与内溶酶体功能和自噬的蛋白质。溶酶体蛋白水解酶在一种 酸性pH，以及来自无脊椎动物模型的数据表明，年龄和压力会导致溶酶体失去 酸性，导致功能受损；然而，这些发现与人类衰老和疾病的相关性 目前还不清楚。溶酶体蛋白水解酶活性的区域差异可能是导致选择性易感性的原因 大脑某些区域对蛋白质聚集体的积累；然而，局部溶酶体的功能是 没有完全表现出特征，因此很难被理解。总而言之，这暗示了一个诱人的假设-- 溶酶体蛋白水解酶表达的区域性差异使某些神经元更容易受到 随年龄增长溶酶体碱化所致的溶酶体功能障碍。为了验证这一假设，Aim 1利用 新型溶酶体pH报告器FIRE-PHLY(报告溶酶体pH的荧光指示剂)可 描述衰老和淀粉样β蛋白蓄积对溶酶体pH的影响。目标2将确定区域 溶酶体结合对衰老脑组织中溶酶体蛋白水解酶活性和表达的影响 分离、免疫组织化学和空间转录。这项研究产生的数据可以是 用于提出衰老和疾病中溶酶体功能障碍的新模型，并确定新的治疗方法 神经退行性疾病的神经保护靶点。