ApoE Regulation of Alpha-Synuclein Pathology in Parkinson Disease Dementia

7.项目摘要/摘要 这个辅导式职业发展奖的目标是促进候选人向独立的过渡 作为一名研究神经退行性变分子机制的内科科学家。应聘者为医学博士/博士 有神经退行性疾病研究背景的神经科医生。这个奖将帮助候选人 实现他的短期目标，获得帕金森病分子发病机制的研究经验 并协助他向拥有独立实验室的调查员过渡。该奖项还将 帮助候选人实现成为一名成功和富有成效的医生的长期目标- 科学家，学术神经学的领军人物。拟议的研究将处于的环境 指挥是杰出的。这位候选人的主要导师大卫·霍尔茨曼博士是一位享誉国际的 科学家和神经学家，在培训初级教员方面有卓越的记录。候选人的 职业发展计划还包括来自多名医生-科学家在所有阶段的结构化指导 资历和与丰富和支持的教职员工的接触，确保候选人在以下方面有榜样 职业发展轨迹的全貌。指导性学习，在科学会议上展示工作，以及 在负责任的研究行为方面的严格培训将确保平衡发展。建议数 研究将检测载脂蛋白E(ApoE)在调节聚集和病理过程中的作用 α-突触核蛋白(α-Syn)的扩散，这是一种与帕金森病(PD)、帕金森病痴呆有关的蛋白质 (PDD)和路易体痴呆(DLB)。α-Syn从天然单体到聚集体的聚集 寡聚体被认为是有毒的，并导致神经元功能障碍。这一过程由其他人调节 包括伴侣蛋白在内的蛋白质。几项遗传学研究指出，载脂蛋白Eε4等位基因是最强的 阿尔茨海默病的遗传风险因素，也是帕金森病患者发展为痴呆症的风险因素。APOE为AND 已知调节淀粉样β蛋白(Aβ)病理，帕金森病患者通常患有αSYN和Aβ 病理上，但重要的是，载脂蛋白E在PDD和DLB中的风险效应似乎独立于Aβ 病理学。本项目的目标是验证载脂蛋白E亚型差异调节α系统的假说 通过稳定有害的低聚中间体进行聚集。第二个假设是载脂蛋白E调节 α-syn在体内的病理构象在细胞间的传播。建议的实验是 旨在阐明载脂蛋白E和α系统之间潜在的新关系，最终目标是 确定可用于治疗由病理性聚集引起的疾病的治疗靶点 αSyn.职业发展奖是为应聘者提供有价值研究的理想机制。 培训将补充他在运动障碍方面的临床重点，并将有助于发展一套 将基础科学发现转化为神经退行性疾病患者的有效疗法。

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.