Hyaluron as a regulator of chemotherapy-induced changes in neurogenesis

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PROJECT SUMMARY In response to the COVID-19 pandemic, the Oregon Health and Science University (OHSU) made the decision to shut down laboratories and all but essential experiments in mid-March. The impact of this decision for this project was that tumor-bearing mice that had been housed for over seven months while developing mammary tumors for this project had to be euthanized before the experiments in aim 1 of this grant could be completed. We are now repeating aim 1 of the project with modified operations now allowed at OHSU. The purpose of this administrative supplement is to provide the funding needed to complete aim 2 of this project. Post-chemotherapy induced cognitive impairment, also called “chemobrain,” affects large numbers of cancer patients and survivors, and is characterized by 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 stemcells (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 hypothesis that chemotherapy alters the HA-based hippocampal extracelluar matrix either by increasing hyaluronidase activity or decreasing HA synthesis, leading to the disruption of HA in the SGZ, increased NSC proliferation, delayed or aberrant neuronal differentiation, and the eventual exhaustion of NSCs and reduced neurogenesis. We will test this hypothesis in a rodent model of chemotherapy with the goal of developing strategies that can enhance or protect neurogenesis during cancer therapies. We will: (1) Test the hypothesis that chemotherapy leads to the induction of hyaluronidases and the accumulation of specific HA digestion products in the hippocampus; and (2) 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.