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

家长奖概述：家长奖中概述的研究重点是 激活TRPV1离子通道增加脑血流量的机制探讨 并在促进大脑低灌流的情况下保持大脑健康。我们的工作表明，这 CBF调节的新途径可能在发生急性血压下降时至关重要，例如， 在失血性休克期间。重要的是，与我们的合作者大卫·朱利叶斯教授合作，我们 已经成功地产生了一种FLOXED-TRPV1小鼠品系。这一突破使我们能够生产出 条件性平滑肌特异性TRPV1基因敲除(SM-TRPV1-KO)小鼠以及感觉神经元特异性 缺乏TRPV1的动物。这些新的小鼠品系正在与体内和体外结合使用 脑血流和神经血管偶联的测量，脑健康的免疫组织化学评估和 认知功能的行为测试。 补编与AD/ADRD的相关性：本补编(NOT-AG-20-034)的目的是 扩展这些研究，并确定TRPV1通道是否对 与AD/ADRD相关的认知衰退和痴呆之前的CBF和神经血管耦合。 具体目标1：阐明TRPV1通道对CBF缺陷的影响 血管性认知障碍与痴呆症(VCID)和阿尔茨海默病(AD)。的目标是 本研究的目的是剖析血管和非血管TRPV1通道对因子的有利作用。 与VCID相关的认知功能下降之前的CBF下降。使用我们最新开发的 组织特异性TRPV1缺陷小鼠喂饲VCID诱导的高胆固醇饲料和转基因(5XFAD)AD 模型小鼠，我们将进行多层次的机制研究，导致局部和 全球CBF监管。具体地说，我们将检验以下假设：平滑肌TRPV1的激活 全身血管系统中的通道可以防止CBF的全球性下降。具体目标2：澄清 TRPV1通道对大鼠行为障碍和脑结构损伤的改善作用 VCID和AD模型小鼠。在这里，我们将使用一组行为测试来阐明TRPV1的好处 通道活动对VCID和AD模型小鼠认知功能的保护作用。行为测试将是 随后对脑白质和灰质进行了全面的检查，以及对 血管系统的结构完整性。该方案将提供前所未有的TRPV1通道分辨率 对脑血流调节和脑健康的影响。确定ASM TRPV1在HAS期间促进CBF方面的关键作用 提供丰富的新信息对AD/ADRD患者个人和我们的 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.