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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Alzheimer&apos 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

项目摘要

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.

项目概要/摘要该提案提出了一个关于溶酶体研究的五年研究职业发展计划 pH 值及其在衰老和疾病中的作用，以扩大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临床研究员记忆与衰老部门的概述提案以 Lane-Donovan 博士之前的研究为基础。 AD 小鼠模型方面的经验，以获得由她的导师团队代表的新专业领域神经病学系的主要导师 Aimee Kao 博士和联合导师 Anna Molofsky 博士分别在加州大学旧金山分校的精神病学领域进行了拟议的实验、教学工作和学术培训。技能将为 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医学科学家领导者。随着我国人口老龄化，与老龄化相关的神经退行性疾病的负担不断增加衰老如何促进某些大脑区域的蛋白质聚集——更重要的是，如何扭转这种影响——当蛋白质聚集时，蛋白质聚集体会积聚仍然未知。溶酶体中蛋白酶的降解受损，AD 的几个遗传风险因素编码参与溶酶体功能和自噬的蛋白质在一定条件下发挥最佳作用。酸性 pH 值和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其活性酸性，导致功能受损；然而，这些发现与人类衰老和疾病的相关性溶酶体蛋白酶活性的区域差异可能导致选择性脆弱性。某些大脑区域会聚集蛋白质；然而，区域溶酶体功能是没有得到充分的表征，因此人们对其知之甚少，这表明了一个诱人的假设—— 溶酶体蛋白酶表达的区域变异性使某些神经元更容易受到随着年龄的增长，溶酶体碱化导致溶酶体功能障碍。为了检验这一假设，目标 1 利用了这一点。新型溶酶体 pH 报告基因 FIRE-pHLy（报告溶酶体 pH 值的荧光指示剂）描绘衰老和β淀粉样蛋白积累对溶酶体 pH 值的影响，目标 2 将确定区域。通过结合溶酶体来改变衰老大脑中溶酶体蛋白酶的活性和表达本研究产生的数据可以是分离、免疫组织化学和空间转录组学。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中神经保护的目标。