Hyaluron as a regulator of chemotherapy-induced changes in neurogenesis

透明质酸作为化疗引起的神经发生变化的调节剂

• 批准号: 10346925
• 负责人: Larry S. Sherman
• 金额: $ 18.41万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10346925
• 关键词: Administrative Supplement; Adult; Affect; Animals; Area; Biochemical; Biological; Biological Assay; Brain; CD44 Antigens; CD44 gene; COVID-19 pandemic; Cancer Patient; Cancer Survivor; Catabolism; Cell Differentiation process; Cell Maturation; Chemotherapy-Oncologic Procedure; Cognitive deficits; Coupled; Data; Digestion; Exposure to; Extracellular Matrix; Fluorouracil; Funding; Generations; Glycosaminoglycans; Goals; Grant; Health Sciences; High Dose Chemotherapy; Hippocampus (Brain); Hyaluronan; Hyaluronidase; Impaired cognition; Impairment; Individual; Laboratories; Lead; Link; Mammary Neoplasms; Measures; Molecular Sieve Chromatography; Mus; Neuronal Differentiation; Neurons; Oregon; Patients; Pharmaceutical Preparations; Pharmacology; Play; Quality of life; Reporting; Rodent Model; Role; Severities; Signal Transduction; Synapses; TLR2 gene; TLR4 gene; Testing; Time; Universities; adult neurogenesis; base; cancer therapy; chemobrain; chemotherapy; cognitive function; dentate gyrus; efficacy testing; excitatory neuron; exhaustion; experimental study; granule cell; hyaluronan synthase 1; improved; improved outcome; inhibitor/antagonist; light scattering; nerve stem cell; neurogenesis; novel; operation; prevent; receptor; receptor expression; relating to nervous system; response; stem cells; tumor

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.

项目摘要 为了回应COVID-19大流行，俄勒冈州健康与科学大学（OHSU）做出了决定 在3月中旬关闭实验室和所有基本实验。这个决定的影响 项目是在乳房中饲养七个月以上的含有七个月以上的肿瘤小鼠 该项目的肿瘤必须安乐死，然后才能完成本赠款的AIM 1实验。 现在，我们正在重复该项目的AIM 1，现在允许在OHSU进行修改的操作。这个目的 行政补充是提供完成该项目的AIM 2所需的资金。 化学疗法后诱导的认知障碍，也称为“ Chemobrain”，会影响大量 癌症患者和幸存者，其特征是癌症化疗后认知缺陷。这些 缺陷可以持续数年，并显着影响受影响患者的生活质量。最近的 研究结果表明，神经发生下的下降，特别是通过下晶中的神经元干细胞（NSC） 海马齿状回（DG）的区域（SGZ），在治疗后导致认知功能障碍 许多不同的化学疗法剂。我们的初步数据表明糖胺聚糖 透明质酸（HA）在用普通化疗剂5-氟尿嘧啶治疗的小鼠的齿状回合中降低 （5-FU）。 SGZ中HA的破坏会导致NSC增殖增加和神经元数量增加 在齿状回的颗粒细胞层中延迟成熟的祖细胞。同样，小鼠缺乏 主要的跨膜HA受体CD44表明SGZ的NSC增殖增加并延迟 神经元祖细胞在齿状回中的成熟。这些小鼠还表现出与认知缺陷有关的 改变海马功能。 这些数据支持化学疗法改变基于HA的海马的假设 通过增加透明质酸酶活性或降低HA合成，导致 SGZ中HA的破坏，NSC增殖增加，延迟或异常神经元 分化以及NSC的事件耗尽并减少了神经发生。我们将测试这个 在化学疗法的啮齿动物模型中的假设，其目的是制定可以增强或保护的策略 癌症治疗过程中的神经发生。我们将：（1）检验化学疗法导致诱导的假设 透明质酸酶和海马中特定HA消化产物的积累； （2）测试 化学疗法诱导的HA消化的假设导致异常的成人神经发生。 这些研究总共有可能揭示出海马的新机制 神经发生在Chemobrain的个体中受到干扰，并将开始测试干扰的效率 透明质酸酶活性是增强接受化疗的癌症患者神经发生的一种手段。