# Therapeutic Irradiation and Brain Functions

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $351,621

## Abstract

Project Summary
 Therapeutic irradiation is commonly used to treat both primary and metastatic brain tumors and can cause
a number of late effects including progressive cognitive dysfunction. There is no treatment currently available
that can even partially reverse cognitive changes observed after radiation injury. Specifically, irradiation of the
temporal lobe can profoundly affect the cellular structures mediating learning and memory. Ionizing radiation
has also been consistently shown to activate several neuroinflammatory signaling cascades that can impact
multiple neural processes and synaptic transmission ultimately causing disruptions in hippocampal function.
Notably, resident microglia and infiltrating monocytes, the key cellular player in neuroinflammatory processes,
have distinct embryological origins and also fulfill different functions. The mechanism/s by which activation of
the inflammatory response affect cognitive functions after brain irradiation and the specific role of different
myeloid cells remain elusive. Thus, there is a clear need to understand the mechanisms of radiation injury and
inflammation to develop strategies for preventing cognitive decline following cranial irradiation.
 Recent work from our group during the previous funding period has shed light in these questions and
revealed specific problems in the cellular and molecular mechanisms underlying radiation-induced memory
deficits. Specifically our data demonstrates a direct link between CCL2/CCR2 and cognition. These results
provide a mechanistic link between peripheral innate immune system and cognition after brain irradiation. In
the current proposal we will evaluate the central hypothesis that therapeutic doses of cranial irradiation induce
infiltration of peripheral monocytes that modifies the resident inflammatory response and promotes synaptic
dysfunction and long term cognitive deficits.
 Aim 1: Determine the kinetics and inflammatory phenotype of radiation-induced myeloid cell alterations
after single and hypofractionated therapeutic doses of irradiation.
 Aim 2: Evaluate the role of peripheral monocyte recruitment into the brain as a mechanistic driver of
radiation-induced altered synaptic and cognitive functions.
 Aim 3: Determine if temporary depletion of myeloid cells prevent the loss of synaptic function and cognition
after single and hypofractionated doses of radiation.
 Very little is known in regard to the evolution of radiation induced pathophysiology in the context of
peripherally derived macrophage accumulation or inflammation, and how this relates to altered synaptic and
cognitive function. Our final therapeutic goal is to modify the cognitive changes observed after radiation injury.

## Key facts

- **NIH application ID:** 10053714
- **Project number:** 5R01CA213441-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** NALIN GUPTA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $351,621
- **Award type:** 5
- **Project period:** 2016-12-09 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053714

## Citation

> US National Institutes of Health, RePORTER application 10053714, Therapeutic Irradiation and Brain Functions (5R01CA213441-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10053714. Licensed CC0.

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