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

家长奖概要：家长奖中概述的研究重点是 研究TRPV 1离子通道激活增加脑血流量（CBF）的机制 并在促进脑灌注不足的条件下维持脑健康。我们的研究表明， CBF调节的新途径可能在血压急性下降期间至关重要，例如， 在失血性休克期间。重要的是，与我们在这个项目上的合作者，大卫朱利叶斯教授，我们 已经成功地产生了一个被感染的TRPV 1小鼠品系。这一突破使我们能够生产 条件性平滑肌特异性TRPV 1敲除（SM-TRPV 1-KO）小鼠，以及感觉神经元特异性 TRPV 1缺陷动物。这些新的小鼠品系正在与体内和离体组合使用。 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 补充资料与AD/ADRD的相关性：本补充资料（NOT-AG-20-034）的目的是 扩展这些研究，并确定TRPV 1通道是否提供保护性益处， 脑血流和神经血管偶联在AD/ADRD相关认知减退和痴呆之前的作用 具体目的1：阐明TRPV 1通道对CBF缺陷的影响， 血管性认知障碍伴痴呆（VCID）和阿尔茨海默病（AD）。的目标 本研究的目的是分析血管和非血管TRPV 1通道对以下因素的有益作用： 导致CBF降低，这先于认知下降相关的VCID。利用我们新开发的 组织特异性TRPV 1缺陷小鼠，喂食VCID诱导的高胆固醇饮食和转基因（5XFAD）AD 模型小鼠，我们将进行多层次的机制，有助于赤字的地方和 全球CBF法规。具体来说，我们将测试以下假设：平滑肌TRPV 1的激活 全身脉管系统中的通道防止CBF的整体下降。具体目标2：阐明 TRPV 1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，使用一组行为测试，我们将阐明TRPV 1的好处， 在VCID和AD模型小鼠中保持认知功能的通道活性。行为测试将是 随后对脑白色物质和灰质进行全面检查，并检查 脉管系统的结构完整性。该提案将提供前所未有的TRPV 1通道分辨率 影响CBF调节和大脑健康。确定ASM TRPV 1在促进CBF过程中的关键作用， 有可能为个体AD/ADRD患者提供大量有益的新信息， 整个社会。

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.