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

这个指导职业发展奖的目标是促进候选人的过渡到独立 作为一名研究神经炎症和神经退行性变的分子机制的医生科学家。的 候选人是具有神经退行性疾病研究背景的MD/PhD神经学家。该奖项将 帮助候选人实现他的短期目标，以获得在分子发病机制的研究经验， 阿尔茨海默病（AD）样病理模型中的神经免疫活化和神经变性， 协助他过渡到一个独立实验室的调查员。该奖项还将有助于定位 候选人，以实现他的长期目标，成为一个成功的和富有成效的医生，科学家和领导者 学术神经学进行拟议研究的环境是杰出的。的 候选人的主要导师，大卫霍尔茨曼博士，是一位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良好的记录。候选人的职业发展计划包括 来自约翰·莫里斯博士的结构化共同导师，他也是一位国际知名的神经学家和临床医生， 科学家，谁将监督候选人的临床培训和临床研究技能的发展。Drs. 霍尔茨曼和莫里斯有一个共同指导许多初级教师成功的独立记录 神经病学的研究生涯教学式学习，在科学会议上介绍工作，以及严格的培训 负责任地进行研究将确保均衡发展。这项研究将审查 25-羟基胆固醇（25-HC）在调节ApoE依赖性淀粉样蛋白神经免疫应答中的作用 病理学和tau介导的神经变性。多种证据表明，免疫激活 介质是AD病理学的关键调节剂。然而，小胶质细胞在调节AD中的确切作用 发病机制仍然难以解析，部分原因是小胶质细胞功能在模型中的差异性作用。 淀粉样变性和tau蛋白病。小胶质细胞对淀粉样蛋白和tau蛋白沉积的反应依赖于载脂蛋白E 如通过其中ApoE表达被遗传缺失的实验所证明的，ApoE的表达是遗传缺失的。25-HC仅生产 小胶质细胞是小胶质细胞反应的有效调节剂，与自身免疫性疾病的发病机制有关。 神经系统疾病和调节ApoE的生产。这个项目的目标是测试假设， 小胶质细胞产生25-HC调节ApoE依赖性神经炎性反应和神经退行性变 淀粉样蛋白和tau蛋白沉积的小鼠模型。阐明25-HC和ApoE在这些过程中的作用， 深入了解AD病理生物学，最终应该指向可以利用的新的治疗靶点 来治疗AD和相关的痴呆症这个职业发展奖是一个理想的机制， 候选人具有宝贵的研究培训，这将补充他在衰老和痴呆症的临床重点， 将帮助培养将基础科学发现转化为针对患有以下疾病的患者的有效疗法的技能 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.