Supplemental Proposal for HL142888: Role of vascular and non-vascular TRPV1 channels in AD/ARD

HL142888 的补充提案：血管和非血管 TRPV1 通道在 AD/ARD 中的作用

• 批准号: 10289453
• 负责人: GEORGE C WELLMAN
• 金额: $ 39万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289453
• 关键词: Acute; Affect; Afferent Neurons; Alzheimer' s Disease; Alzheimer' s disease model; American; Animal Model; Animals; Arteries; Award; Behavioral; Blood; Blood Pressure; Blood Vessels; Blood flow; Brain; Brain Injuries; Cations; Cause of Death; Cerebrovascular Circulation; Cerebrovascular system; Cholesterol; Cognition; Dementia; Diet; Drops; Etiology; Generations; Genetic; Goals; Head; Healthcare; Hemorrhagic Shock; Impaired cognition; Impairment; Individual; Innate Immune System; Ion Channel; Knock-out; Knockout Mice; LoxP-flanked allele; Measurement; Modeling; Mouse Strains; Mus; Neuraxis; Outcome; Pain Research; Parents; Pathway interactions; Patients; Permeability; Regulation; Resolution; Role; Shunt Device; Smooth Muscle; Societies; Structure; Sympathetic Nervous System; TRPV1 gene; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Vascular Cognitive Impairment; Vascular resistance; Work; behavior test; brain health; cerebral hypoperfusion; cerebrovascular; cognitive function; combat; design; effective therapy; gray matter; improved; in vivo; insight; lens; mouse model; neurovascular coupling; novel; novel strategies; parent grant; preservation; white matter

SUMMARY OF THE PARENT AWARD: The studies outlined in the parent award are focused on investigating the mechanisms by which the activation of TRPV1 ion channels increase cerebral blood flow (CBF) and maintain brain health during conditions promoting cerebral hypoperfusion. Our work indicates that this novel pathway of CBF regulation may be critical during acute drops in blood pressure that occur, for example, during hemorrhagic shock. Importantly, working with our collaborator on this project, Prof. David Julius, we have succeeded in the generation of a floxed-TRPV1 mouse strain. This breakthrough has enabled us to produce conditional smooth muscle-specific TRPV1-knockout (SM-TRPV1-KO) mice, as well as sensory neuron-specific TRPV1-deficient animals. These novel mouse strains are being used in combination with in vivo and ex vivo measurements of CBF and neurovascular coupling, immunohistochemical assessment of brain health and behavioral tests of cognitive function. RELEVANCE OF SUPPLEMENT TO AD/ADRD: The purpose of this Supplement (NOT-AG-20-034) is to extend these studies and determine whether TRPV1 channels provide a protective benefit against deficits in CBF and neurovascular coupling that precede cognitive decline and dementia associated with AD/ADRD. Specific Aim 1: To elucidate the impact of TRPV1 channels on CBF deficits contributing to vascular cognitive impairment with dementia (VCID) and Alzheimer's Disease (AD). The goal of this aim is to dissect the beneficial effects of vascular and non-vascular TRPV1 channels against factors contributing to decreases in CBF, which precede cognitive decline associated VCID. Using our newly developed tissue-specific TRPV1 deficient mice fed a VCID-inducing high cholesterol diet and transgenic (5XFAD) AD model mice, we will undertake a multi-level examination of mechanisms contributing to deficits in local and global CBF regulation. Specifically, we will test the following hypothesis: Activation of smooth muscle TRPV1 channels in the systemic vasculature protect against global declines in CBF. Specific Aim 2: To elucidate the impact of TRPV1 channels to ameliorate behavioral deficits and structural brain damage in VCID and AD model mice. Here, using a battery of behavioral tests we will elucidate the benefit of TRPV1 channel activity in preserving cognitive function in VCID and AD model mice. The behavioral tests will be followed by a comprehensive examination of brain white matter and grey matter, as well an examination of the structural integrity of the vasculature. This proposal will provide unprecedented resolution of TRPV1 channel impact on CBF regulation and brain health. Identifying a key role for ASM TRPV1 in promoting CBF during has the potential to provide a wealth of new information of great benefit to individual AD/ADRD patients and our society at large.

父母奖的摘要：父母奖中概述的研究重点是 研究TRPV1离子通道激活增加脑血流（CBF）的机制 并在促进大脑灌注灌注的条件下保持大脑健康。我们的工作表明这 在血压急性下降期间，CBF调节的新途径可能至关重要，例如 在出血性休克期间。重要的是，与我们的合作者一起在这个项目上合作，David Julius教授，我们 已经成功地生成了Floxed-Trpv1小鼠菌株。这一突破使我们能够生产 有条件的平滑肌特异性TRPV1敲除（SM-TRPV1-KO）小鼠以及感觉神经元特异性 TRPV1缺陷动物。这些新型的小鼠菌株已与体内和离体结合使用 CBF和神经血管耦合的测量，脑健康的免疫组织化学评估 认知功能的行为测试。 补充与AD/ADRD的相关性：此补充的目的（NOT-AG-20-034）是 扩展这些研究并确定TRPV1渠道是否提供了针对缺陷的保护益处 与AD/ADRD相关的认知下降和痴呆之前的CBF和神经血管耦合。 特定目的1：阐明TRPV1通道对CBF缺陷的影响 痴呆症（VCID）和阿尔茨海默氏病（AD）的血管认知障碍。目标 该目的是剖析血管和非血管TRPV1通道对因素的有益作用 在认知下降之前与VCID相关的CBF下降。使用我们新开发的 组织特异性的TRPV1缺乏小鼠喂养VCID诱导的高胆固醇饮食和转基因（5XFAD）AD 模型小鼠，我们将对有助于本地和局部缺陷的机制进行多层次检查 全球CBF法规。具体而言，我们将测试以下假设：平滑肌TRPV1的激活 系统性脉管系统中的渠道可防止CBF全球下降。特定目标2：阐明 TRPV1通道对改善行为缺陷和结构性脑损伤的影响 VCID和AD模型小鼠。在这里，使用一系列行为测试，我们将阐明TRPV1的好处 在VCID和AD模型小鼠中保留认知功能的通道活动。行为测试将是 然后对脑白质和灰质进行全面检查，以及对 脉管系统的结构完整性。该提案将提供TRPV1渠道前所未有的解决方案 对CBF调节和大脑健康的影响。确定ASM TRPV1在促进CBF的关键角色中 为个人广告/ADRD患者和我们的 整个社会。