# Circadian regulation of cancer therapy-associated neuroinflammation

> **NIH NIH R21** · STANFORD UNIVERSITY · 2022 · $228,831

## Abstract

Recent advances in cancer therapy have increased survivability of numerous pediatric and adult cancers. By
2023, over 20 million cancer survivors will live in the United States. Unfortunately, the vast majority of these
individuals will exhibit some indication of sustained neurological deficiency, clinically called cancer therapy-
related cognitive impairment (CRCI). These impairments include deficits in memory, learning, attention,
executive function, information processing, language, and multitasking. Despite the myriad suspected causes of
CRCI, one of the main commonalities is a persistent neuroinflammatory state following cancer treatment. How
this sustained neuroinflammation is mediated remains a critical gap in our understanding of the underlying
biology of CRCI. Our previous work in a preclinical mouse model demonstrated that the commonly used
chemotherapeutic agent, methotrexate (MTX), induces tri-glial dysregulation that is dependent on the direct
activation of microglia, the resident immune cells of the central nervous system. Systemic MTX administration
results in persistent microglial pan activation which promotes astrocyte reactivity and decreased OPC density
and differentiation into myelin-forming oligodendrocytes, leading to thinner myelin. MTX-induced aberrant
myelination causes persistent cognitive deficits associated with CRCI, including decrements in short-term
memory and attention for up to six months post-treatment. Preliminary data from our lab demonstrates that this
microglial activation, and consequent dysregulation of oligodendrocyte lineage cells, is time-of-day dependent,
suggesting that the sustained microglial activation and clinical deficiency associated with CRCI may be regulated
in a circadian manner and thus susceptible to chronomodulation. The objective of this proposal is to determine
if MTX chemotherapy drives intrinsic changes to the microglial transcriptome and alters the structure or function
of the BBB to sustain the activation of microglia associated with CRCI. Our central hypothesis is that
chemotherapy-induced chronic neuroinflammation is modulated by circadian regulation of microglia and the
BBB. Our approach to testing this hypothesis is to expose microglia in vitro and in vivo to MTX chemotherapy at
different circadian phases and analyze the transcriptional profile of isolated microglia and BBB endothelial cells,
as well as assess BBB permeability and integrity. The rationale for this approach is that information gleaned from
the results will contribute mechanistic understanding into the intrinsic and microenvironmental modulators of
neuroinflammatory microglia following cancer therapy. Upon completion of this proposal, we expect to have
identified how circadian modulation dictates microglial activation to chemotherapy. There remains an urgent
need to define the underlying mechanisms of neuroinflammation mediating the persistent neurological
dysregulation in CRCI in preclinical models of cancer therap...

## Key facts

- **NIH application ID:** 10510232
- **Project number:** 1R21CA267135-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Erin G Valdez
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $228,831
- **Award type:** 1
- **Project period:** 2022-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10510232

## Citation

> US National Institutes of Health, RePORTER application 10510232, Circadian regulation of cancer therapy-associated neuroinflammation (1R21CA267135-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10510232. Licensed CC0.

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