Microvascular Neuroimaging in Age-related Alzheimer's Disease and Tauopathies

年龄相关性阿尔茨海默病和 Tau蛋白病的微血管神经影像学

• 批准号: 10738372
• 负责人: Ning Hua
• 金额: $ 12.11万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738372
• 关键词: 3xTg-AD mouse; Ablation; Acceleration; Address; Advisory Committees; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Atherosclerosis; Attention; Attenuated; Biology; Biophysics; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Boston; Brain; Brain Injuries; Brain region; Calibration; Cardiovascular system; Career Choice; Career Mobility; Clinical; Dementia; Development; Diagnosis; Diagnostic; Diffusion Magnetic Resonance Imaging; Disease Progression; Doctor of Philosophy; Economic Burden; Environment; Extravasation; Faculty; Foundations; Funding; Goals; Health; Hippocampal Formation; Hippocampus; Imaging Techniques; Inductively Coupled Plasma Mass Spectrometry; Injury; Investigation; Knowledge; Lasers; Learning; Link; Liquid substance; Magnetic Resonance Imaging; Measurement; Measures; Memory; Memory Loss; Memory impairment; Mentored Research Scientist Development Award; Mentors; Methods; Microvascular Dysfunction; Mission; Nervous System Trauma; Neurodegenerative Disorders; Outcome; Pathology; Performance; Permeability; Play; Positioning Attribute; Predisposition; Radiology Specialty; Recovery; Research; Research Activity; Research Personnel; Resolution; Resources; Risk; Risk Factors; Role; Scientist; Societies; Specific qualifier value; Stress; Structure; System; Tauopathies; Testing; Therapeutic; Time; Training; Training Activity; Transgenic Mice; Trauma; Trauma patient; Traumatic Brain Injury; United States National Institutes of Health; Universities; Work; abeta accumulation; age related; aging brain; blood-brain barrier disruption; blood-brain barrier permeabilization; brain magnetic resonance imaging; career; contrast enhanced; early onset; experimental study; head impact; high risk; hippocampal atrophy; hippocampal subregions; hyperphosphorylated tau; imaging biomarker; improved; in vivo; invention; mass spectrometric imaging; mechanical load; medical schools; mouse model; neuroimaging; neuroimaging marker; neurovascular; novel; professor; skills; tau Proteins; tau-1; therapeutically effective; vascular injury; white matter

PROJECT SUMMARY / ABSTRACT Ning Hua, PhD, is an MRI scientist whose overarching career goal is to become an independent investigator in the field of microvascular dysfunction and its relationship to Alzheimer’s disease (AD) and aging brain. The proposed K01 research combines advanced in vivo dynamic contrast enhanced (DCE)-MRI and novel ex vivo Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS), and aims to explore how trauma- induced hippocampal microvascular injury accelerates memory deficits, AD-related pathology, and white matter degeneration. Candidate: Dr. Hua is an Assistant Professor at the Department of Radiology of Boston University (BU), Chobanian & Avedisian School of Medicine. She gained her PhD in Biophysics, and her previous training was focused on cardiovascular MRI and arterial atherosclerosis. This K01 proposal will build on her previous training in MRI, programming, and vascular biology, with 4 training goals to facilitate her transition into neuroimaging and neurodegenerative diseases and towards career independence: 1) Learn the biology and pathology underlying AD; 2) Learn relevant experimental skills in neurotrauma and AD mouse models; 3) Advance her skills in neuroimaging; 4) Prepare for independent research and career track. Mentors/Environment: Dr. Hua and her primary mentor, Lee E. Goldstein, MD, PhD, have assembled a strong mentor/advisory team to guide her through the K01 training and research activity. The proposed plan will leverage resources of the newly established Center for Translational Neuroimaging (BU) and the NIH-NIA supported BU Alzheimer’s Disease Center. BU and the Department of Radiology are committed to supporting junior faculty through internal funding, administrative assistance, and structured opportunities. Research: Currently, it is unclear if blood-brain-barrier (BBB) dysfunction is a mechanistic driver for the acceleration of AD after neurotrauma. I hypothesize that hippocampus is vulnerable to neurotrauma, and that resulting hippocampal microvascular leakage will accelerate local accumulation of amyloid-β and phosphorylated-tau, as well as accelerate white matter degeneration, ultimately leading to accelerated memory deficits in AD. The experiments will be carried in a well-characterized transgenic mouse model of AD (3xTg-AD) with and without well-calibrated traumatic brain impacts. In vivo MRI measured hippocampal leakage will be correlated with memory deficits measured by Barnes Maze test (Aim 1). Ex vivo LA-ICP-MS measured subregional BBB leakage in hippocampus will be correlated with regional accumulations of amyloid and tau pathology (Aim 2). Finally, ex vivo diffusion MRI will be used to assess how hippocampal injury accelerates white matter degeneration, especially in the white matter bundles connecting to the hippocampus and playing an important role in memory and learning (Aim 3). Summary: This K01 proposal utilizes advanced imaging techniques to detect hippocampal BBB leakage, and its relation to the acceleration of AD. It will facilitate Dr. Hua’s career transition to independence in the research of neuroimaging and AD.

项目摘要/摘要 宁华博士是一名核磁共振科学家，他的首要职业目标是成为一名独立的调查员 微血管功能障碍及其与阿尔茨海默病(AD)和脑老化的关系。这个 建议的K01研究结合了先进的体内动态对比增强(DCE)-MRI和新的体外研究 激光消融电感耦合等离子体质谱(LA-ICPMS)，旨在探索创伤是如何- 诱发的海马区微血管损伤加速记忆障碍、AD相关病理和脑白质 退化。候选人：华博士是波士顿大学放射科助理教授 (BU)，乔班和阿维迪斯医学院。她获得了生物物理学博士学位，以及之前的训练 重点是心血管核磁共振和动脉粥样硬化。这份K01提案将建立在她之前的基础上 核磁共振、编程和血管生物学方面的培训，有4个培训目标，以促进她过渡到 神经影像和神经退行性疾病和走向职业独立：1)学习生物学和 阿尔茨海默病的病理学基础；2)学习神经创伤和AD小鼠模型的相关实验技能；3) 提高她在神经成像方面的技能；4)为独立研究和职业发展做准备。 导师/环境：华博士和她的主要导师，李·E·戈尔茨坦，医学博士，已经组建了一个强大的 指导她完成K01培训和研究活动的导师/顾问团队。拟议的计划将 利用新成立的翻译神经成像中心(BU)和NIH-NIA的资源 支持北卡罗来纳大学阿尔茨海默病中心。BU和放射科致力于支持 通过内部资助、行政援助和有组织的机会培养初级教师。研究： 目前尚不清楚血脑屏障(BBB)功能障碍是否是AD加速的机械性驱动因素 在神经创伤之后。我假设海马体很容易受到神经创伤，而由此产生的海马体 微血管渗漏将加速淀粉样蛋白β和磷酸化tau的局部积聚，以及 加速脑白质退化，最终导致AD患者记忆力减退。这些实验 将在特征良好的AD转基因小鼠模型(3xTg-AD)中携带，无论是否经过良好校准 创伤性脑撞击。活体MRI测量的海马区漏液将与记忆障碍相关 采用Barnes迷宫测试(目标1)。LA-ICPMS测定海马区血脑屏障渗漏的体外研究 将与淀粉样蛋白和tau病理的区域堆积相关(目标2)。最后，体外扩散 MRI将被用来评估海马区损伤如何加速脑白质退化，特别是在 白质束连接到海马体，在记忆和学习中发挥重要作用(目的 3)。摘要：本K01方案利用先进的成像技术检测海马区血脑屏障渗漏， 以及它与AD加速的关系。它将促进华博士的职业生涯向独立的过渡 神经影像与阿尔茨海默病研究。