Radiation and Oxidative Stress Effects on Neurogenesis

辐射和氧化应激对神经发生的影响

• 批准号: 6826250
• 负责人: JOHN R. FIKE
• 金额: $ 34.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826250
• 关键词: apoptosis; cell proliferation; cognition disorders; dentate gyrus; flow cytometry; free radical oxygen; genetically modified animals; hippocampus; immunocytochemistry; ionizing radiation; laboratory mouse; mitochondria; neurogenesis; oxidative stress; radiobiology; superoxide dismutase; terminal nick end labeling

DESCRIPTION (provided by applicant): Ionizing irradiation is commonly used in the management of malignant brain tumors. Although effective in many cases, therapeutic irradiation of the brain can cause significant normal tissue damage. In general, overt tissue injury occurs after relatively high doses, but less severe injury can occur after lower doses, which can lead to cognitive impairment. The pathogenesis of radiation-induced cognitive impairment is not clear but may involve neural subgranular zone (SGZ) precursor cells in the dentate gyrus of the hippocampus. These cells participate in the process or neurogenesis, continually producing cells that are able to migrate away and differentiate into mature dentate granule cells. Loss of dentate granule cells and/or proliferating precursor cells is associated with specific types of cognitive dysfunction. We have shown that neural precursor cells in the SGZ are exquisitely sensitive to irradiation, undergoing apoptosis after clinically relevant doses. Furthermore, we have shown that after irradiation there is a prolonged reduction in overall cell proliferation in the SGZ and a dose-related decrease in the production of new neurons. Lastly, we have data suggesting that oxidative stress may be involved in radiation-induced changes in the SGZ and in hippocampal precursor cell cultures. It is our contention that oxidative stress plays a critical role in the acute radiation response of proliferating neural precursors and in later reductions in hippocampal neurogenesis. Further we assert that inhibition of neurogenesis will lead to cognitive impairment. It is our overall objective to determine how oxidative stress affects the radiation response of SGZ precursor cells and their progeny and to identify compounds/strategies that will enable us to ameliorate the adverse effects of irradiation on hippocampal neurogenesis and cognitive function. We have defined 4 specific aims to address our objective: 1) Quantify the relationship between deficiencies in site-specific superoxide dismutases (SODs) and acute, radiation induced effects on proliferating SGZ precursor cells and their progeny; 2) Establish the relationship between site-specific SODs and hippocampal neurogenesis 2-6 months following-x-irradiation; 3) Quantify the ability of antioxidant SOD/catalase mimetic treatment to reduce SGZ apoptosis and to ameliorate radiation-induced inhibition of neurogenesis; and 4) Determine whether SOD mimetic treatment results in improved cognitive function in mice treated with x-rays.

描述（由申请人提供）：电离辐射通常用于治疗恶性脑肿瘤。虽然在许多情况下有效，但脑的治疗性照射可引起显著的正常组织损伤。一般来说，在相对高剂量后会发生明显的组织损伤，但在较低剂量后会发生不太严重的损伤，这可能导致认知障碍。辐射引起的认知障碍的发病机制尚不清楚，但可能涉及海马齿状回的神经颗粒下区（SGZ）前体细胞。这些细胞参与神经发生过程，不断产生能够迁移并分化为成熟齿状颗粒细胞的细胞。齿状颗粒细胞和/或增殖前体细胞的丢失与特定类型的认知功能障碍有关。我们已经表明，在SGZ的神经前体细胞是非常敏感的辐射，发生凋亡后，临床相关剂量。此外，我们已经表明，照射后，有一个长期的减少，在SGZ的整体细胞增殖和剂量相关的减少，在新的神经元的生产。最后，我们有数据表明，氧化应激可能参与辐射诱导的变化，在SGZ和海马前体细胞培养。我们认为，氧化应激在神经前体细胞增殖的急性辐射反应和海马神经发生的后期减少中起着至关重要的作用。此外，我们断言，抑制神经发生将导致认知障碍。我们的总体目标是确定氧化应激如何影响SGZ前体细胞及其后代的辐射反应，并确定使我们能够改善辐射对海马神经发生和认知功能的不良影响的化合物/策略。我们确定了4个具体的目标来实现我们的目标：1）量化位点特异性超氧化物歧化酶（SOD）缺陷与急性辐射诱导的SGZ前体细胞及其后代增殖效应之间的关系：2）建立位点特异性SOD与X射线照射后2-6个月海马神经发生之间的关系; 3）定量抗氧化剂SOD/过氧化氢酶模拟物处理减少SGZ细胞凋亡和改善辐射诱导的神经发生抑制的能力;和4）确定SOD模拟物处理是否导致用X射线处理的小鼠的认知功能改善。