Functional deficits in neurovascular coupling in Alzheimer's disease

阿尔茨海默病神经血管耦合的功能缺陷

基本信息

批准号：
10349996
负责人：
Amreen Mughal
金额：
$ 14.08万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349996
关键词：
Action Potentials Acute Advisory Committees Age Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Astrocytes Award Back Behavioral Biology Blood Vessels Blood capillaries Blood flow Brain Calcium Signaling Capillary Endothelial Cell Cell membrane Cerebrovascular Circulation Cerebrovascular system Cessation of life Chronic Cognition Data Dementia Development Dinoprostone Disease Electrophysiology (science)Endothelial Cells Endothelium Environment Event Functional disorder Healthcare Systems Hyperemia ITPR1 gene Image Image Analysis Impaired cognition Impairment Incidence Injections Interruption Investigation Ion Channel Measurement Measures Mediating Mediator of activation protein Membrane Memory Mentors Metabolic Mission Molecular Mus Neurons Nitric Oxide Nutrient Oxygen Pathogenesis Pathology Pathway interactions Phase Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipids Postdoctoral Fellow Potassium Preparation Process Public Health Regulation Research Research Personnel Senile Plaques Sensory Signal Transduction Supplementation Testing Therapeutic Therapeutic Intervention Time Training Programs United States United States National Institutes of Health Variant Vascular Cognitive Impairment Work aging population analog arteriole attenuation base behavior test blood flow measurement brain endothelial cell career career development cognitive function density design extracellular familial Alzheimer disease functional restoration improved in vivo in vivo imaging millisecond mouse model neuron loss neurovascular coupling novel parenchymal arterioles pressure prevent relating to nervous system response restoration skills treatment strategy

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is a major public health burden in the United states with a death toll that continues to increase steeply. While cerebral blood flow (CBF) is substantially reduced in AD, the vascular pathophysiology is not yet entirely characterized. We have identified two neurovascular coupling (NVC) mechanisms essential in regulation of CBF: electrical signaling (mediated by K+), which is rapid (millisecond time scale) and acts over long distances, and Ca2+ signaling (mediated by GqPCR agonists), which is slow (seconds) and acts locally. Yet how- these NVC mechanisms are altered in AD is incompletely understood. Therefore, the long-term objective of this proposal is to use a familial mouse model of AD (5xFAD) to determine functional deficit in NVC mechanisms in AD and design therapeutic strategies to restore these impairments. Preliminary data show that electrical signaling is reduced in 5xFAD mice due to impaired Kir2.1 channel function and restored by supplementation of membrane phospholipid; PIP2—an essential component for Kir2.1 channel function. Hence, I have a novel hypothesis that deficit in functional hyperemia in AD is the result of vascular PIP2 depletion, which cripples electrical and Ca2+ signaling control of blood flow. Accordingly, I will determine the molecular mechanisms through which loss of PIP2 disrupts these processes and evaluate whether PIP2 supplementation restores CBF control and in turn, improve cognitive function in 5xFAD mice. I will test this hypothesis by executing the following specific aims: 1) Elucidate mechanisms associated with defective electrical signaling in AD, 2) Evaluate the impact of AD pathology on brain endothelial Ca2+ activity, and 3) Determine the effect of PIP2 restoration on NVC in AD. To execute these specific aims, I will combine of cutting edge in vivo and ex vivo experimental approaches with behavioral testing. Collectively, this proposal will identify vascular functional deficits in AD and PIP2 based therapeutic intervention for restoration of CBF and in turn, cognitive function in AD. This proposal aligns with one of the NIH mission statements to prevent and effectively treat Alzheimer's disease by 2025. This current proposal will contribute Dr. Amreen Mughal’s career development as she transitions from a postdoctoral fellow to an independent researcher. Adding to her strong background in vascular biology, Amreen will develop new skills in the state-of-the-art image analysis and behavioral testing. Dr. Mark T. Nelson, an expert in ion channels, Ca2+ signaling, and vascular biology, will mentor Amreen’s scientific development and transition to independence during this award. To enhance the Candidate’s training, the program additionally enlists a career advisory team, including Drs. Anne Joutel, Sayamwong Hammack, and Severin Schneebeli. The productive research environment with the backing of the NIH Pathway to Independence Award (K99/R00) will allow the Candidate to develop her own research niche and successfully transition as an independent research investigator.

项目摘要阿尔茨海默氏病（AD）是美国的主要公共卫生伯恩伦，死亡人数继续陡峭增加。虽然AD中的脑血流（CBF）大大降低，但血管生理学尚未完全表征。我们已经确定了两种神经血管耦合（NVC）机制 CBF的调节：电信（由K+介导的），这是快速（毫秒时间尺度），并且作用于长距离和Ca2+信号传导（由GQPCR激动剂介导），这是缓慢（秒）并在局部起作用的。然而但是，这些NVC机制在AD中发生了改变。因此，长期目标该建议的是使用AD的家庭鼠标模型（5xFAD）来确定NVC中的功能不足 AD和设计理论策略的机制恢复了这些障碍。初步数据显示由于KIR2.1通道函数受损，在5xFAD小鼠中降低了电信号传导，并通过补充膜磷脂； PIP2 - KIR2.1通道函数的重要组件。因此，我有一个新颖的假设，即AD功能性充血不足是血管PIP2部署的结果，哪个剪辑了血流的电气和Ca2+信号传导控制。彼此之间，我将确定分子损失PIP2破坏这些过程并评估PIP2是否补充的机制恢复CBF控制，然后改善5XFAD小鼠的认知功能。我将通过执行来检验此假设以下具体目的：1）阐明与AD中的电信号有缺陷相关的机制，2）评估AD病理对脑内皮Ca2+活性的影响，3）确定PIP2的影响 AD中的NVC恢复。为了执行这些特定的目标，我将结合体内前沿的尖端行为测试的实验方法。总的来说，该建议将确定血管功能基于AD和PIP2的缺陷，用于恢复CBF的治疗干预措施，而认知功能又广告。该提案与NIH任务陈述之一一致，以预防和有效地对待阿尔茨海默氏症到2025年。当前的建议将为Amreen Mughal博士的职业发展做出贡献独立研究人员的博士后研究员。为了增加她在血管生物学方面的良好背景，艾姆林将在最先进的图像分析和行为测试中发展新技能。专家Mark T. Nelson博士在离子渠道，CA2+信号传导和血管生物学中，心理Amreen的科学发展和过渡将在此奖励期间独立。为了增强候选人的培训，该计划还招募了职业咨询团队，包括Drs。 Anne Joute，Sayamwong Hammack和Severin Schneebeli。这 NIH独立奖（K99/R00）的支持，生产性研究环境将允许候选人开发自己的研究利基市场，并成功过渡为独立研究研究者。