# Radiation-induced astrocyte dysfunction and cognitive decline

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2022 · $342,913

## Abstract

Whole brain irradiation (WBI) leads to progressive dementia in ~50% of brain tumor patients who survive long-
term after treatment, at least in part, due to dysregulation of CBF. Although the specific mechanisms for WBI-
induced deceases in CBF and cognitive decline are not yet known, there is increasing evidence that alterations of
the neurovascular unit play a crucial role. The objective of this proposal is to elucidate the mechanistic role of
irradiation-induced astrocyte dysfunction in cognitive impairment. The central hypothesis is that irradiation
causes astrocyte senescence and subsequent dysfunction, altering the production of vasodilator mediators
and impairing neurovascular coupling (NVC) responses. The resulting neurovascular dysfunction contributes to
decline in CBF and cognitive impairments. The proposed work is novel in that it will be the first to demonstrate
that radiation-induced astrocyte senescence is a key driver of the effects of WBI on the brain. The results will
likely identify specific mechanisms and reveal potential therapies that are capable of improving cerebral blood
supply and restoring learning and memory. The following aims are proposed: 1) Elucidate the cellular 
mechanisms underlying WBI-induced impairment of NVC responses. The working hypothesis is that WBI impairs both
eicosanoid-mediated and purinergic components of NVC responses. To test this hypothesis in a clinically 
relevant mouse model of WBI, pathways contributing to NVC responses will be assessed using laser speckle 
contrast imaging, pharmacological tools and LC/MS/MS-based measurement of gliotransmitter release. The 
impact of pharmacological up-regulation of NVC responses on cognitive function of WBI-treated mice will be 
determined. 2) Determine how irradiation-induced senescence alters astrocyte function and phenotype. It is 
predicted that irradiation induces senescence in astrocytes, which impairs cellular energy metabolism and the
production/release of ATP and alters the cellular secretory profile, dysregulating the synthesis of vasoactive
lipid mediators. To test these hypotheses senescent astrocytes will be isolated from WBI-treated mice and 
primary human astrocyte cultures will be irradiated in vitro. We will combine advanced cellular imaging 
techniques and cutting-edge proteomics and biochemistry to investigate cellular energetics, gene expression and
secretome signatures, the regulation of ATP release and the synthesis of lipid mediators. 3) Determine 
whether elimination of senescent cells improves NVC and cognitive function in WBI-treated mice. It is hypothesized
that activation of p16-dependent cellular senescence programs is responsible for WBI-induced neurovascular
dysfunction and cognitive impairment. It is expected that elimination of senescent cells, either through genetic
manipulation (p16-3MR mouse model) or by pharmacological means will restore neurovascular function and
improve cognition in WBI-treated mice. Together, the prop...

## Key facts

- **NIH application ID:** 10320428
- **Project number:** 5R01NS100782-05
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** ZOLTAN Istvan UNGVARI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $342,913
- **Award type:** 5
- **Project period:** 2017-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320428

## Citation

> US National Institutes of Health, RePORTER application 10320428, Radiation-induced astrocyte dysfunction and cognitive decline (5R01NS100782-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320428. Licensed CC0.

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