Radiation and Oxidative Stress Effects on Neurogenesis

说明(申请人提供)：电离辐射是治疗恶性脑肿瘤的常用方法。尽管在许多情况下有效，但治疗性脑照射可能会导致严重的正常组织损伤。一般来说，相对高剂量后会出现明显的组织损伤，但较低剂量后可能会发生较轻的损伤，这可能会导致认知障碍。放射性认知损害的发病机制尚不清楚，但可能涉及海马齿状回中的神经颗粒下带(SGZ)前体细胞。这些细胞参与这一过程或神经发生，不断产生能够迁移并分化为成熟的齿状颗粒细胞的细胞。齿状颗粒细胞和/或增殖的前体细胞的丢失与特定类型的认知功能障碍有关。我们已经证明，SGZ中的神经前体细胞对辐射非常敏感，在临床相关剂量后发生凋亡。此外，我们还发现，在照射后，SGZ的整体细胞增殖持续减少，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，氧化应激在增殖的神经前体细胞的急性辐射反应中起关键作用，并在随后的海马神经发生中减少。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利影响的化合物/策略。我们已经确定了4个具体目标来解决我们的目标：1)量化部位特异性超氧化物歧化酶(SODS)缺陷与辐射对SGZ前体细胞及其后代增殖的急性影响之间的关系；2)建立部位特异性超氧化物歧化酶与海马神经发生之间的关系；3)定量抗氧化剂超氧化物歧化酶/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；以及4)确定模拟SOD处理是否可改善接受X射线照射的小鼠的认知功能。

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.