Radiation and Oxidative Stress Effects on Neurogenesis

描述（由申请人提供）：电离照射通常用于恶性脑肿瘤的治疗。虽然在许多情况下是有效的，但脑部的治疗性照射会造成严重的正常组织损伤。一般来说，在相对高剂量后会发生明显的组织损伤，但在较低剂量后可能发生较轻的损伤，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，但可能与海马齿状回的神经亚颗粒带（SGZ）前体细胞有关。这些细胞参与神经发生过程，不断产生能够迁移并分化成成熟的齿状颗粒细胞的细胞。牙状颗粒细胞和/或增殖前体细胞的丧失与特定类型的认知功能障碍有关。我们已经证明，SGZ中的神经前体细胞对照射非常敏感，在临床相关剂量后发生凋亡。此外，我们已经表明，在照射后，SGZ的整体细胞增殖长期减少，新神经元的产生与剂量相关。最后，我们有数据表明氧化应激可能参与辐射诱导的SGZ和海马前体细胞培养的变化。我们认为，氧化应激在增殖神经前体的急性辐射反应和后来海马神经发生的减少中起着关键作用。我们进一步断言，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，并确定化合物/策略，使我们能够改善照射对海马神经发生和认知功能的不利影响。我们确定了4个具体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x射线照射后2-6个月部位特异性sod与海马神经发生的关系；3)量化抗氧化SOD/过氧化氢酶模拟处理减少SGZ细胞凋亡和改善辐射诱导的神经发生抑制的能力；4)确定超氧化物歧化酶模拟治疗是否能改善x射线治疗小鼠的认知功能。

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.