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

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2021 · $390,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10289453
- **Project number:** 3R01HL142888-03S1
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** GEORGE C WELLMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,000
- **Award type:** 3
- **Project period:** 2019-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10289453

## Citation

> US National Institutes of Health, RePORTER application 10289453, Supplemental Proposal for HL142888: Role of vascular and non-vascular TRPV1 channels in AD/ARD (3R01HL142888-03S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10289453. Licensed CC0.

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