# Hyaluron as a regulator of chemotherapy-induced changes in neurogenesis

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $184,075

## Abstract

Post-chemotherapy induced cognitive impairment, also called “chemobrain,” affects large numbers of
cancer patients and survivors, and is characterized by subjectively reported and objectively measured
cognitive deficits following cancer chemotherapy. These deficits can last for up to several years and
significantly impact the quality of life of affected patients. Recent findings have indicated that declines in
neurogenesis, particularly by neural stem cells (NSCs) in the subgranular zone (SGZ) of the hippocampal
dentate gyrus (DG), contribute to cognitive dysfunction following treatment with a number of different
chemotherapy agents. Our preliminary data indicate that the glycosaminoglycan hyaluronan (HA) is reduced in
the dentate gyri of mice treated with a common chemotherapy agent, 5-fluorouracil (5-FU). Disruption of HA in
the SGZ leads to increased NSC proliferation and increased numbers of neuronal progenitors whose
maturation is delayed in the granule cell layer of the dentate gyrus. Similarly, mice lacking the major
transmembrane HA receptor CD44 demonstrate increased NSC proliferation in the SGZ and delayed neuronal
progenitor cell maturation in the dentate gyrus. These mice also demonstrate cognitive deficits related to
altered hippocampal function.
 These data support the novel hypothesis that chemotherapy can alter the HA-based
hippocampal extracelluar matrix either by increasing hyaluronidase activity or decreasing HA
synthesis, leading to the disruption of HA in the SGZ. This disruption would initially lead to increased
NSC proliferation and delayed or aberrant neuronal differentiation, and the eventual exhaustion of
NSCs and reduced neurogenesis. Our aim in the current application is to test this hypothesis in a rodent
model of chemotherapy with the long-term goal of developing strategies that can enhance or protect
neurogenesis during cancer therapies. Our specific aims are: (1) To test the hypothesis that chemotherapy
leads to the induction of hyaluronidases and the accumulation of specific HA digestion products in the
hippocampus; and (2) To test the hypothesis that chemotherapy-induced HA digestion leads to aberrant adult
neurogenesis.
 All together, these studies have the potential to reveal a novel mechanism by which hippocampal
neurogenesis is disrupted in individuals with chemobrain and will begin to test the efficacy of interfering with
hyaluronidase activity as a means of enhancing neurogenesis in cancer patients undergoing chemotherapy.

## Key facts

- **NIH application ID:** 9873941
- **Project number:** 5R21CA223461-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Larry S. Sherman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $184,075
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873941

## Citation

> US National Institutes of Health, RePORTER application 9873941, Hyaluron as a regulator of chemotherapy-induced changes in neurogenesis (5R21CA223461-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9873941. Licensed CC0.

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