# The role of cellular senescence in chemotherapy-related cognitive impairment

> **NIH NIH F32** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $76,487

## Abstract

PROJECT SUMMARY
The etiology of chemotherapy-related cognitive impairment (CRCI) is understudied despite the growing clinical
awareness of its contribution to patient morbidity. Disease-modifying therapies to ameliorate CRCI are urgently
needed. However, development of these therapies is limited by an incomplete understanding of the underlying
mechanisms of CRCI. The long-term goal is to identify novel cellular mechanisms that contribute to CRCI. The
overall objective of this application is to identify the role of cellular senescence in CRCI and define the microglial
contribution to senescence after chemotherapy exposure. The central hypothesis is that cellular senescence
mediates cognitive deficits in CRCI and that microglia promote chemotherapy-induced senescence in the brain.
The rationale for the proposed research is based on preliminary data showing increased expression of
senescence markers in various cell populations and evidence of increased neuroinflammation in the brains of
human autopsy patients with history of chemotherapy compared to controls. The central hypothesis will be tested
by performing two specific aims in a mouse model of CRCI that I have developed: (1) identify the contribution of
senescence to CRCI and (2) determine the role of microglia in the development of chemotherapy-induced
senescence in the brain. For the first aim, CRCI will induced in transgenic p16-3MR mice to determine if ablation
of senescent cells rescues the cognitive phenotype of chemotherapy-treated mice. For the second aim, microglia
in a CRCI mouse model will be pharmacologically depleted with PLX5622 (an inhibitor of colony-stimulating
factor 1 receptor (CSF1R) that selectively targets microglia) to determine if reducing the number of microglia
rescues cognition and reduces measures of senescence after chemotherapy. In both aims, senescence in
multiple cell lineages of the central nervous system (CNS) will be assessed using a variety of molecular and
immunofluorescent and senescence-associated beta-galactosidase staining techniques. The approach is
innovative because the powerful transgenic p16-3MR mice line will be used to identify the role of senescence in
CRCI and the role of microglia in mediating chemotherapy-induced senescence in CNS populations, both of
which have not been assessed to date. Furthermore, the chemotherapeutic agents used in this study are highly
clinically relevant to a number of malignancies. The proposed research is significant because if chemotherapy-
induced senescence in the brain adversely affects cognition, then senolytic therapies may be a promising new
strategy to reduce the morbidity of CRCI. Finally, data collected from this proposal will form the basis of my future
K08 application and my research focus as an independent clinician scientist.

## Key facts

- **NIH application ID:** 10141408
- **Project number:** 1F32CA257210-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Matthew Torre
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $76,487
- **Award type:** 1
- **Project period:** 2021-02-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141408

## Citation

> US National Institutes of Health, RePORTER application 10141408, The role of cellular senescence in chemotherapy-related cognitive impairment (1F32CA257210-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10141408. Licensed CC0.

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