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

25-羟基胆固醇在调节 ApoE 依赖性阿尔茨海默病相关发病机制中的作用

基本信息

批准号：
10381730
负责人：
Justin Matthew Long
金额：
$ 15.08万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10381730
关键词：
25-hydroxycholesterol APP-PS1 Adrenoleukodystrophy Affect Aging Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid Amyloid deposition Amyloidosis Amyotrophic Lateral Sclerosis Anti-Inflammatory Agents Apolipoprotein E Astrocytes Autoimmune Diseases of the Nervous System Award Basic Science Biological Response Modifiers Caregiver Burden Cells Cholesterol Clinical Clinical Research Coculture Techniques Complement Data Dementia Deposition Development Development Plans Disease Disease associated microglia Doctor of Philosophy Ensure Environment Enzymes Faculty Genes Genetic Goals Human Immune Inflammasome Inflammatory Innate Immune Response International K-Series Research Career Programs Knockout Mice Laboratories Learning Mediating Mentors Mentorship Methods Microglia Mixed Function Oxygenases Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuroimmune Neurologist Neurology Neurons Nuclear RNA Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Peripheral Phagocytes Phenotype Physicians Play Positioning Attribute Process Production Protein Isoforms Public Health Research Research Personnel Research Training Role Scientist Senile Plaques Source Structure Supervision Tauopathies Testing Therapeutic Intervention Training Transcript Transgenic Mice Transgenic Organisms Translating Work amyloid pathology apolipoprotein E-3 apolipoprotein E-4 autoimmune pathogenesis career career development cell motility cerebral amyloidosis clinical candidate clinical development cost cytokine disability effective therapy experience experimental study extracellular immune activation insight macrophage meetings mouse model neurodegenerative phenotype neuroinflammation neurotoxic new therapeutic target novel prevent response responsible research conduct sarkosyl single cell sequencing skills tau Proteins tau aggregation tau mutation transcriptome sequencing transcriptomics β-amyloid burden

项目摘要

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.

这个指导职业发展奖项的目标是促进候选人向独立过渡