Hyaluron as a regulator of chemotherapy-induced changes in neurogenesis

项目摘要 为了应对COVID-19大流行，俄勒冈州健康与科学大学（OHSU）做出了这一决定 在三月中旬关闭了实验室和所有必要的实验。这一决定的影响 一个研究项目是，在患有乳腺癌的小鼠中， 该项目的肿瘤必须在完成该补助金目标1的实验之前进行安乐死。 我们现在正在重复项目的目标1，OHSU现在允许修改操作。这样做的目的 行政补助金的目的是提供完成该项目目标2所需的资金。 化疗后引起的认知障碍，也称为“化学脑”，影响大量的 癌症患者和幸存者，其特征在于癌症化疗后的认知缺陷。这些 缺陷可持续长达数年，并显著影响受影响患者的生活质量。最近 研究结果表明，神经发生的下降，特别是神经干细胞（NSC）在亚颗粒 海马齿状回（DG）的区域（SGZ），导致认知功能障碍， 一些不同的化疗药物。我们的初步数据表明， 用普通化疗剂5-氟尿嘧啶治疗的小鼠齿状回中的透明质酸（HA）减少 （5-FU）。SGZ中HA的破坏导致增加的NSC增殖和增加的神经元数量。 在齿状回颗粒细胞层中成熟延迟的祖细胞。同样，缺乏 主要的跨膜HA受体CD 44显示SGZ中NSC增殖增加， 齿状回神经元祖细胞成熟。这些小鼠还表现出与 海马功能的改变 这些数据支持了化疗改变了海马HA区的假设。 通过增加透明质酸酶活性或减少HA合成， SGZ中HA的破坏，增加的NSC增殖，延迟或异常的神经元 分化，以及最终耗尽的NSC和减少的神经发生。我们将测试这个 在啮齿类动物模型中的化疗假设，目的是开发可以增强或保护 癌症治疗中的神经发生。我们将：（1）检验化疗导致诱导的假设 透明质酸酶和特定HA消化产物在海马中的积累;和（2）测试海马中的透明质酸酶活性。 假设化疗诱导的HA消化导致异常的成体神经发生。 总之，这些研究有可能揭示一种新的机制， 神经发生在具有chemobrain的个体中被破坏，并且将开始测试干扰 透明质酸酶活性作为增强接受化疗的癌症患者神经发生的手段。

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.