# Chemogenetic neurovascular oxidative stress: neurodegeneration and cardiac remodeling

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $776,474

## Abstract

Oxidative stress is a hallmark of neurodegeneration and has been implicated in the pathobiology of vascular
contributions to cognitive impairment and dementia (VCID). Our “chemogenetic” approach allows us to
dynamically modulate reactive oxygen species (ROS) in target cells in vivo using the yeast enzyme D-amino
acid oxidase (DAAO) to produce the ROS hydrogen peroxide (H2O2). We generated two new transgenic mouse
lines that express DAAO by crossing a conditionally activatable DAAO transgenic mouse line (which we
developed) with commercially available mouse lines expressing Cre recombinase under control of two distinct
putatively “endothelial cell-specific” Cdh5 or Tie2 promoters. Both the DAAO-TGCdh5 and DAAO-TGTie2 lines
express DAAO and generate H2O2 in endothelial cells. Within 2 days of providing D-alanine to DAAO-TGCdh5
mice, the animals develop a striking sensory ataxia, and have a highly specific pattern of neurodegeneration and
mitochondrial disarray in dorsal root ganglia and nodose (vagal sensory) ganglia. Importantly, DAAO-TGCdh5
mice treated with D-alanine also develop cardiac hypertrophy. The combination of sensory neuropathy and
cardiac hypertrophy is similar to the phenotype of Friedreich’s ataxia, the most common form of hereditary ataxia
in humans. By contrast, the DAAO-TGTie2 transgenic line, which expresses DAAO in endothelium under control
of the Tie2 promoter, shows no ataxia, has no transgene expression in DRG, and does not develop cardiac
hypertrophy. But the DAAO-TGTie2 mice does develop marked disruption of the blood barrier following long-term
D-alanine feeding. Here we propose studies to test the hypotheses that neurovascular oxidative stress leads to
neurodegeneration, BBB disruption, cognitive dysfunction, and cardiac hypertrophy. We propose to pursue
transcriptomic, proteomic, metabolomic, and biochemical studies of DRG, nodose ganglia, brain, and cardiac
tissues following chemogenetic oxidative stress in vivo, and we will study the behavioral and physiological
phenotypes in the DAAO-TGCdh5 and DAAO-TGTie2 mouse lines. We will identify the temporal sequence and the
molecular mechanisms whereby neurovascular oxidative stress causes degeneration of DRG and nodose
ganglia and leads to cardiac hypertrophy. We will establish the pathways by which vascular oxidative stress
disrupts the BBB and leads to cognitive impairment. The Specific Aims are: Aim 1: Identify the molecular
mechanisms whereby neurovascular oxidative stress causes degeneration of DRG; Aim 2: Characterize the
molecular processes whereby neurovascular oxidative stress causes disruption of the blood-brain barrier and
leads to cognitive impairment; Aim 3: Define the pathways whereby neurovascular oxidative stress causes
cardiac hypertrophy. The proposed studies may lead to the identification of new pharmacological targets for
prevention and treatment of Alzheimer’s Disease and related dementias, Friedreich’s ataxia, adverse cardiac
remodeling, and the many ot...

## Key facts

- **NIH application ID:** 10798756
- **Project number:** 1R01NS131182-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Thomas Michel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $776,474
- **Award type:** 1
- **Project period:** 2024-02-02 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798756

## Citation

> US National Institutes of Health, RePORTER application 10798756, Chemogenetic neurovascular oxidative stress: neurodegeneration and cardiac remodeling (1R01NS131182-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10798756. Licensed CC0.

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