ApoE Regulation of Alpha-Synuclein Pathology in Parkinson Disease Dementia

ApoE 对帕金森病痴呆中 α-突触核蛋白病理学的调节

• 批准号: 9295190
• 负责人: Albert A Davis
• 金额: $ 17.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295190
• 关键词: Affect; Age-Months; Alleles; Alzheimer' s Disease; Amyloid Fibrils; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Attenuated; Award; Basic Science; Binding; Biochemical; Biosensor; Brain; Brain region; Caregivers; Cell Line; Cells; Clinical; Co-Immunoprecipitations; Code; Comorbidity; Complement; Corpus striatum structure; Data; Dementia; Development; Development Plans; Disease; Doctor of Philosophy; Ensure; Environment; Event; Exposure to; Faculty; Fluorescence; Genes; Genetic study; Gliosis; Goals; Growth; Health; Human; Human Genetics; Idiopathic Parkinson Disease; In Vitro; Individual; Injectable; Injection of therapeutic agent; International; K-Series Research Career Programs; Kinetics; Knock-in; Knock-in Mouse; Knowledge; Laboratories; Learning; Lewy Bodies; Lewy Body Dementia; Life; Lipids; Literature; Measures; Mentors; Mentorship; Modification; Molecular; Molecular Chaperones; Molecular Conformation; Monitor; Morbidity - disease rate; Movement Disorders; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurologist; Neurology; Neuronal Dysfunction; Neurons; Nursing Homes; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathologic; Pathology; Patients; Phase; Physicians; Physiological; Positioning Attribute; Process; Protein Conformation; Protein Isoforms; Proteins; Recruitment Activity; Regulation; Reporting; Research; Research Personnel; Research Training; Risk; Risk Factors; Role; SNCA gene; Scientist; Structure; Surface Plasmon Resonance; Techniques; Testing; Toxic effect; Training; Transgenic Mice; Translating; Work; alpha synuclein; apolipoprotein E-3; apolipoprotein E-4; beta amyloid pathology; beta pleated sheet; brain cell; career; career development; cell type; cost; design; disability; effective therapy; experience; experimental study; genetic risk factor; in vivo; meetings; monomer; neuron loss; novel; prevent; protein aggregation; responsible research conduct; role model; skills; tetramethylrhodamine; therapeutic target

7. Project Summary/Abstract The goal of this mentored career development award is to facilitate the candidate's transition to independence as a physician-scientist studying molecular mechanisms of neurodegeneration. The candidate is an MD/PhD neurologist with a background in neurodegenerative disease research. The award will help the candidate achieve his short-term goal, to gain research experience in the molecular pathogenesis of Parkinson disease and dementia and facilitate his transition to an investigator with an independent laboratory. The award will also help position the candidate to achieve his long-term goal of becoming a successful and productive physician- scientist and a leader in academic neurology. The environment in which the proposed research will be conducted is outstanding. The candidate's primary mentor, Dr. David Holtzman, is an internationally respected scientist and neurologist with a proven track record of excellence in training junior faculty. The candidate's career development plan also includes structured mentorship from multiple physician-scientists at all stages of seniority and exposure to a rich and supportive faculty, ensuring that the candidate has role models along the full spectrum of the career trajectory. Didactic learning, presentation of work at scientific meetings, and rigorous training in the responsible conduct of research will ensure a balanced development. The proposed research will examine the role of apolipoprotein E (apoE) in regulating the aggregation and pathological spread of alpha synuclein (αSyn), a protein implicated in Parkinson disease (PD), Parkinson disease dementia (PDD), and dementia with Lewy bodies (DLB). The aggregation of αSyn from its native monomer form into oligomers is thought to be toxic and to contribute to neuronal dysfunction. This process is regulated by other proteins including chaperone proteins. Several genetic studies point to the APOE ε4 allele, the strongest genetic risk factor for Alzheimer disease, as a risk factor for developing dementia in PD as well. APOE is and is known to regulate amyloid-beta (Aβ) pathology and individuals with PD often have comorbid αSyn and Aβ pathology, but importantly, the risk effect of APOE in PDD and DLB appears to be independent of Aβ pathology. The goal of this project is to test the hypothesis that apoE isoforms differentially regulate αSyn aggregation by stabilizing a harmful oligomeric intermediate. A secondary hypothesis is that apoE regulates the propagation of pathologic conformations of αSyn from cell to cell in vivo. The proposed experiments are designed to elucidate a potential novel relationship between apoE and αSyn, with the ultimate goal of identifying therapeutic targets that can be leveraged to treat diseases caused by pathologic aggregation of αSyn. This career development award is an ideal mechanism to provide the candidate with valuable research training which will complement his clinical focus in movement disorders and will help develop a skill set for translating basic science discoveries into effective therapies for patients with neurodegenerative diseases.

7。项目摘要/摘要 这个讨论职业发展奖的目标是促进候选人向独立的过渡 作为研究神经退行性的分子机制的物理科学家。候选人是MD/PHD 具有神经退行性疾病研究背景的神经科医生。该奖项将帮助候选人 实现他的短期目标，以获得帕金森病分子发病机理的研究经验 痴呆症并促进他向调查员的独立实验室过渡。该奖项也将 帮助候选人实现自己的长期目标，即成为一名成功且富有成效的医生 - 科学家和学术神经病学领导者。拟议研究的环境 进行的是杰出的。候选人的主要导师戴维·霍尔茨曼（David Holtzman）博士是国际尊重的 科学家和神经科医生在培训初级教师方面具有卓越的卓越纪录记录。候选人的 职业发展计划还包括来自多个身体科学家的结构化精神职位 资历和接触富裕和支持的教师，确保候选人在沿途有榜样 全部职业轨迹。教学学习，在科学会议上的工作表现以及 负责任进行研究的严格培训将确保平衡发展。提议 研究将研究载脂蛋白E（APOE）在调节中的作用 α突触核蛋白（αSyn）的传播，一种植入帕金森氏病（PD），帕金森氏病痴呆症的蛋白质 （PDD）和带有路易尸体（DLB）的痴呆症。 αSyn从其天然单体形式的聚集到 低聚物被认为是有毒的，并且会导致神经元功能障碍。这个过程受其他调节 包括伴侣蛋白在内的蛋白质。几项遗传研究指向ApoEε4等位基因，strongst 阿尔茨海默氏病的遗传危险因素，也是PD发展痴呆症的危险因素。 Apoe是和 已知可以调节淀粉样蛋白β（Aβ）病理学和PD的个体通常具有合并症αSyn和Aβ 病理学，但重要的是，PDD和DLB中APOE的风险效应似乎与Aβ无关 病理。该项目的目的是检验APOE同工型对αSyn的调节的假设 通过稳定有害的寡聚中间体来聚集。次要假设是APOE调节 αSyn从体内从细胞到细胞的病理构象的传播。提出的实验是 旨在阐明ApoE和αSyn之间的潜在新型关系，其最终目标是 识别可以利用的治疗靶标，以治疗由病理聚集引起的疾病 αSyn。该职业发展奖是为候选人提供宝贵研究的理想机制 培训将补充他在运动障碍上的临床重点，并将有助于开发一种技能 将基础科学发现转化为神经退行性疾病患者的有效疗法。