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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

基本信息

批准号：
10006865
负责人：
Albert A Davis
金额：
$ 16.86万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10006865
关键词：
Affect Age-Months Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk 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 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 Injections 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&apos s Dementia Pathogenesis Pathologic Pathology Patients Phase Physicians Physiological Positioning Attribute Process Protein Conformation Protein Isoforms Proteins 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 comorbidity cost design disability effective therapy experience experimental study genetic risk factor in vivo meetings monomer neuron loss novel prevent protein aggregation recruit responsible research conduct role model skills tetramethylrhodamine therapeutic target

项目摘要

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.项目总结/摘要这个指导职业发展奖的目标是促进候选人的过渡到独立作为一名研究神经退化分子机制的科学家候选人是MD/PhD 具有神经退行性疾病研究背景的神经学家。该奖项将有助于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和痴呆症，并促进他过渡到一个独立的实验室研究员。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- 科学家和学术神经学的领导者。拟议研究将在其中进行的环境进行得非常出色。候选人的主要导师，大卫霍尔茨曼博士，是一个国际上受人尊敬的科学家和神经学家，在培训初级教师方面有着卓越的记录。候选人的职业发展计划还包括来自多个医生-科学家在各个阶段的结构化指导，资历和接触丰富和支持教师，确保候选人有榜样沿着全方位的职业发展轨迹教学式学习，在科学会议上介绍工作，在负责任地开展研究方面进行严格的培训将确保均衡的发展。拟议研究将检查载脂蛋白E（apoE）在调节聚集和病理过程中的作用。 α突触核蛋白（αSyn）的扩散，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）。αSyn从其天然单体形式聚集成低聚物被认为是有毒的，并导致神经元功能障碍。这一过程受到其他蛋白质，包括伴侣蛋白。一些遗传学研究指出，APOE ε4等位基因，最强的阿尔茨海默病的遗传风险因素，也是PD中发生痴呆的风险因素。APOE是和已知α Syn可调节β淀粉样蛋白（Aβ）病理，PD患者通常伴有αSyn和Aβ共病但重要的是，APOE在PDD和DLB中的风险效应似乎与Aβ无关。病理本项目的目的是验证apoE亚型差异调节αSyn的假说通过稳定有害的低聚物中间体而聚集。第二个假设是apoE调节 αSyn的病理构象在体内从细胞到细胞的传播。建议的实验是旨在阐明apoE和αSyn之间潜在的新关系，最终目标是鉴定可用于治疗由病原体的病理性聚集引起的疾病的治疗靶标，合成α星这个职业发展奖是一个理想的机制，为候选人提供有价值的研究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。