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.

项目概要 为了应对 COVID-19 大流行，俄勒冈健康与科学大学 (OHSU) 做出了决定 在三月中旬关闭实验室和除必要实验之外的所有实验 这一决定对此的影响。 该项目的目的是让患有肿瘤的小鼠在发育乳腺的过程中被圈养七个多月 在完成本次赠款目标 1 的实验之前，必须对这个项目的肿瘤实施安乐死。 我们现在正在重复该项目的目标 1，并在 OHSU 允许修改操作。 行政补充是为了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“化疗脑”，影响大量患者 癌症患者和幸存者，其特点是癌症化疗后认知缺陷。 缺陷可持续长达数年，并严重影响受影响患者的生活质量。 研究结果表明，神经发生的下降，特别是颗粒下神经干细胞（NSC）的下降 海马齿状回（DG）的区域（SGZ），导致治疗后认知功能障碍 我们的初步数据表明糖胺聚糖。 使用常见化疗药物 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 NSC 增殖增加和神经元数量增加。 类似地，缺乏齿状回颗粒细胞层的祖细胞的成熟。 主要跨膜 HA 受体 CD44 证明 SGZ 中 NSC 增殖增加并延迟 这些小鼠的齿状回神经祖细胞的成熟也表现出与认知缺陷相关。 改变海马功能。 这些数据支持化疗改变基于 HA 的海马的假设 通过增加透明质酸酶活性或减少 HA 合成来抑制细胞外基质，从而导致 SGZ 中 HA 的破坏、NSC 增殖增加、神经元延迟或异常 分化，以及神经干细胞最终耗尽和神经发生减少，我们将对此进行测试。 啮齿类动物化疗模型中的假设，旨在制定能够增强或保护化疗的策略 我们将：（1）检验化疗导致诱导的假设。 (2) 测试海马中透明质酸酶的含量和特定 HA 消化产物的积累； 假设化疗诱导的 HA 消化导致异常的成人神经发生。 总而言之，这些研究有可能揭示海马体的一种新机制 具有化学脑的个体的神经发生被破坏，并且将开始测试干扰的功效 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一种手段。