# Leveraging mitochondrial function to combat radiation therapy-induced microvascular disease

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

Every year, an estimated 20,000 of the 200,000 veterans treated for cancer at a Veterans Health
Administration facility receive radiation therapy (RT) as part of their treatment plan. As chemo- and
radiotherapies become more effective, patients are living long enough to develop late adverse effects of
radiation, such as heart failure and cognitive decline after chest and brain irradiation, respectively. These
disorders, termed “normal tissue injury” (NTI), are thought to result from acute radiation damage to the
microvascular endothelium of vessels supplying the otherwise healthy tissues that surround the targeted
cancer. While later-stage NTI has been characterized by decreased capillary density, ischemia, and loss of
normal tissue function, the early damage responses which drive these pathologies remains unclear. Chronic
oxidative stress, initiated by the burst of superoxide and hydroxyl radicals during ionizing radiation exposure, is
a potential driver of progressive damage to the microvascular endothelium. Associations between these
pathways and the decreased blood flow observed after RT have yet to be established. In order to develop
preventative measures and mitigators, early markers of vascular response to RT must be identified, and a
relationship established between them and the late vascular pathologies observed with NTI.
 The objective of the proposed project is to dissect the role of blood flow in the development of normal
tissue injury after radiation therapy, and to determine whether mitigation of oxidative stress can diminish or
eliminate these changes. Chronic oxidative stress in the vascular endothelium has been associated with
diminished vasodilatory capacity and endothelial dysfunction, which may then result in decreased blood flow
after RT. Antioxidants like pharmacological ascorbate (P-AscH-) have been successfully deployed to mitigate
vascular endothelial dysfunction in models of vascular disease like diabetes and hypertension; furthermore, in
clinical studies of cancers like glioblastoma multiforme, treatment with P-AscH- has been shown effective at
improving progression-free and overall survival. We postulate that chronic oxidative stress initiated during RT
is responsible for early perfusion defects, which progress to ischemia and loss of normal tissue function. Our
central hypothesis is that decreased blood flow, which may be mitigated by administration of P-AscH-,
precedes cognitive dysfunction after radiotherapy. This hypothesis is supported by pilot data showing
decreased blood flow as early as 14 days after radiation exposure, before a decrease in cognitive function was
detected 30 days after irradiation of a single hemisphere. The precision targeting provided by our state-of-the-
art small animal irradiator enables dose delivery to a single hemisphere, such that the contralateral hemisphere
can be used as an internal control. Blood flow and tissue oxygenation will be measured in each hemisphere
using laser speckle fl...

## Key facts

- **NIH application ID:** 10557667
- **Project number:** 3I01BX000163-13S1
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Isabella Maria Grumbach
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 3
- **Project period:** 2010-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10557667

## Citation

> US National Institutes of Health, RePORTER application 10557667, Leveraging mitochondrial function to combat radiation therapy-induced microvascular disease (3I01BX000163-13S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10557667. Licensed CC0.

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