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集中在

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.