# Hydrogen peroxide in endothelial function and dysfunction

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $413,067

## Abstract

The parent R01 grant for this Administrative Supplement is supporting studies of an experimental program that uses
chemogenetic approaches to define the roles of reactive oxygen species (ROS) and oxidative stress in the vascular
endothelium. Supplemental funds are now requested to directly extend these studies from the characterization of the
peripheral vascular phenotype to perform studies of mouse behavior in order to define the roles of vascular oxidative
stress in the pathophysiology of Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD).
Oxidative stress has been observed in nearly all animal models of AD/ADRD and also in brain tissues from
human AD/ADRD patients. We plan to exploit novel chemogenetic approaches to generate a new model of
AD/ADRD, with a focus on vascular dementias caused by oxidative stress in the vascular wall.
 The parent R01 proposed studies to develop and characterize the vascular phenotype of a new DAAO-
TGendo transgenic/chemogenetic mouse line that exploits the chemogenetic yeast enzyme D-amino acid oxidase
(DAAO) to generate ROS in vascular endothelium. Here we request an Administrative Supplement that will
extend these studies to test the hypothesis that cerebrovascular oxidative stress causes AD/ADRD. The
proposed studies address one of the target research topic areas that are explicitly listed for this Administrative
Supplement: “Vascular Contributions to Cognitive Impairment and Dementia (VCID)”. The proposed work is likely
to lead to the development of new experimental models for AD/ADRD and to the development of novel
therapeutic targets both within VCID as well as in other AD/ADRD disease states.
 It is important to note that the new DAAO-TGendo transgenic mouse line that we plan to study has already
been generated and characterized, and the scope of the proposed studies has been tightly focused in order to
yield informative results within the one-year time frame supported by the Administrative Supplement. Results
from these studies will set the stage for future experiments to extend chemogenetic approaches into extant
mouse models of AD/ADRD in which oxidative stress has been implicated in disease pathophysiology.
 My laboratory has a long record of basic/translational discovery in cardiovascular disease states, yet we
have limited expertise in study of neurological diseases. We have engaged a key collaborator for these studies:
Professor Dennis Selkoe, MD. Dr. Selkoe is a close colleague at BWH who is an acknowledged world leader in
Alzheimer’s Disease basic/translational research. Dr. Selkoe’s laboratory at BWH is located nearby my own lab,
as is the Anne Romney Center for Neurological Disease (which Dr. Selkoe co-directs)– which includes advanced
neuropathology imaging facilities as well as a sophisticated Mouse Behavior Core Lab.
 The proposed studies will pursue experiments using DAAO-TGendo transgenic mice following the
generation of chronic in vivo chemogenetic oxidative stress in ...

## Key facts

- **NIH application ID:** 10492227
- **Project number:** 3R01HL152173-02S1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Thomas Michel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $413,067
- **Award type:** 3
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492227

## Citation

> US National Institutes of Health, RePORTER application 10492227, Hydrogen peroxide in endothelial function and dysfunction (3R01HL152173-02S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10492227. Licensed CC0.

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