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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目概要/摘要宁华博士是一位 MRI 科学家，其首要职业目标是成为一名独立研究者微血管功能障碍领域及其与阿尔茨海默病（AD）和大脑老化的关系。拟议的 K01 研究结合了先进的体内动态对比增强 (DCE)-MRI 和新颖的离体激光烧蚀电感耦合等离子体质谱 (LA-ICP-MS)，旨在探索创伤如何诱发的海马微血管损伤加速记忆缺陷、AD 相关病理和白质候选人：华博士是波士顿大学放射学系助理教授。她在 Chobanian & Avedisian 医学院获得了生物物理学博士学位，并接受了之前的培训。该 K01 提案将建立在她之前的基础上。 MRI、编程和血管生物学方面的培训，有 4 个培训目标，以帮助她过渡到神经影像和神经退行性疾病以及职业独立：1）学习生物学和 AD基础病理学；2）学习神经创伤和AD小鼠模型的相关实验技能；提高她在神经影像学方面的技能；4）为独立研究和职业发展做好准备。导师/环境：华博士和她的主要导师 Lee E. Goldstein（医学博士、哲学博士）组建了一支强大的团队导师/咨询团队将指导她完成 K01 培训和研究活动。利用新成立的转化神经影像中心 (BU) 和 NIH-NIA 的资源支持 BU 阿尔茨海默病中心和放射科致力于支持。通过内部资助、行政援助和结构化研究机会的初级教师：目前尚不清楚血脑屏障（BBB）功能障碍是否是加速 AD 的机械驱动因素在神经创伤之后，我勇敢地承认海马体很容易受到神经创伤，并且由此产生的海马体微血管渗漏会加速淀粉样蛋白-β和磷酸化-tau蛋白的局部积累，以及加速白质退化，最终导致 AD 中的记忆缺陷加速。将在经过充分校准和未经充分校准的 AD 转基因小鼠模型 (3xTg-AD) 中进行体内 MRI 测量的海马渗漏与记忆缺陷相关。通过 Barnes 迷宫测试（目标 1）测量体外 LA-ICP-MS 测量海马的次区域 BBB 渗漏。将与淀粉样蛋白和 tau 病理学的区域积累相关（目标 2）。 MRI 将用于评估海马损伤如何加速白质变性，特别是在连接海马体的白质束在记忆和学习中发挥重要作用（目标 3) 摘要：该 K01 提案利用先进的成像技术来检测海马 BBB 渗漏，及其与 AD 加速的关系，这将有助于华博士在职业生涯中向独立过渡。神经影像学和AD的研究。