The role of 25-hydroxycholesterol in modulating ApoE-dependent Alzheimer disease-related pathogenesis

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 作为一名内科科学家，研究神经炎症和神经退行性变的分子机制。这个 候选人是医学博士/博士神经学家，有神经退行性疾病研究背景。该奖项将 帮助应聘者实现短期目标，获得在分子发病机制方面的研究经验 阿尔茨海默病(AD)样病理模型中的神经免疫激活和神经变性 协助他转变为拥有独立实验室的调查员。该奖项还将有助于将 实现他成为一名成功和多产的内科科学家和领导者的长期目标的候选人 在学术神经学方面。进行拟议研究的环境非常好。这个 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，拥有 在培训初级教员方面取得了卓越的成绩。候选人的职业发展计划包括 约翰·莫里斯博士的结构化共同指导，他也是一位在国际上受尊敬的神经学家和临床医生- 科学家，他将监督候选人的临床培训和临床研究技能的发展。戴维斯博士。 霍尔茨曼和莫里斯有共同指导无数初级教师成功独立工作的记录。 从事神经学研究的职业。讲授学习、科学会议上的工作报告和严格的培训 在负责任的研究行为中将确保均衡发展。拟议的研究将检查 25-羟基胆固醇(25-HC)在调节ApoE依赖的淀粉样蛋白免疫反应中的作用 病理学和tau介导的神经变性。多条证据表明，免疫系统的激活 中介物是AD病理的重要调节因子。然而，小胶质细胞在调节阿尔茨海默病中所起的确切作用 发病机制仍然很难解析，部分原因是小胶质细胞功能在模型中的不同影响。 淀粉样变性和直肠肌萎缩症。小胶质细胞对淀粉样蛋白和tau沉积的反应依赖于载脂蛋白E (APOE)，载脂蛋白E表达被基因删除的实验证明。25-HC是独家生产的 小胶质细胞是一种强有力的小胶质细胞反应调节剂，与自身免疫的发病机制有关。 神经疾病，调节载脂蛋白E的产生。这个项目的目标是检验这样一个假设 小胶质细胞产生25-HC调节载脂蛋白E依赖的神经炎性反应和神经变性 淀粉样蛋白和tau沉积的小鼠模型。澄清25-HC和ApoE在这些过程中的作用将提供 对AD病理生物学的洞察，最终应该指向可以利用的新的治疗靶点 治疗阿尔茨海默病及相关痴呆。这一职业发展奖是一个理想的机制，可以提供 应聘者接受了有价值的研究培训，这将补充他在老龄化和痴呆症方面的临床重点 将帮助开发一套将基础科学发现转化为有效疗法的技能，适用于患有 神经退行性疾病。

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 neuroinflammation and neurodegeneration. The candidate is a 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 neuroimmune activation and neurodegeneration in models of Alzheimer disease (AD)-like pathology 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 includes structured co-mentorship from Dr. John Morris, also an internationally respected neurologist and clinician- scientist, who will supervise the candidate’s clinical training and development of clinical research skills. Drs. Holtzman and Morris have a track record of co-mentoring numerous junior faculty to successful independent research careers in neurology. 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 25-hydroxycholesterol (25-HC) in modulating the neuroimmune response to ApoE-dependent amyloid pathology and tau-mediated neurodegeneration. Multiple lines of evidence suggest that activation of immune mediators is a critical regulator of AD pathology. However, the exact role that microglia play in modulating AD pathogenesis is still difficult to parse, partly due to discrepant effects of microglial function in models of amyloidosis and tauopathy. Microglial response to amyloid and tau deposition is dependent on apolipoprotein E (ApoE) as evidenced by experiments where ApoE expression is genetically deleted. 25-HC is produced exclusively by microglia, is a potent modulator of microglial response, has been implicated in the pathogenesis of autoimmune neurological disease and modulates the production of ApoE. The goal of this project is to test the hypothesis that microglial production of 25-HC modulates ApoE-dependent neuroinflammatory responses and neurodegeneration in mouse models of amyloid and tau deposition. Clarifying the role of 25-HC and ApoE in these processes will provide insights into AD pathobiology and ultimately should point towards novel therapeutic targets that can be leveraged to treat AD and related dementias. This career development award is an ideal mechanism to provide the candidate with valuable research training which will complement his clinical focus in Aging and Dementia and will help develop a skill set for translating basic science discoveries into effective therapies for patients with neurodegenerative diseases.