RADIATION-INDUCED INJURY IN CEREBRAL ENDOTHELIAL CELLS--ROLE OF OXIDATIVE STRESS

手术后放射治疗是最有效的治疗方法。 恶性脑瘤，但临床可接受的辐射剂量为 这是有限的，因为辐射也会损害正常组织。如果这一损害 可以得到改善，对脑瘤的辐射剂量可能是 增加了，提高了疗效。放射性脑损伤 损害通常包括对脑血管系统的损害，如 血脑屏障明显破坏和脑水肿。在这 研究中，我们希望阐明导致这种敏感性的机制。 对组成脑血管系统的细胞进行辐射。这 研究可能会提出可能的治疗方法，以改善 正常脑的辐射敏感性。我们假设不同的 内源性抗氧化剂水平，如抗坏血酸和促氧化剂， 如天然产生的自由基一氧化氮(NO)，是 对脑血管的任何不同放射敏感性负责 细胞：内源性氧化剂水平的改变可以调节 对辐射敏感。为了验证这一假设，我们将研究辐射。 原代培养的脑血管内皮细胞、星形胶质细胞 和来自正常大鼠和小鼠的周细胞和过度表达的转基因小鼠 人铜锌超氧化物歧化酶 各种抗氧化剂和促氧化剂。我们的具体目标是：1) 原代培养大鼠脑细胞敏感性的定量研究 血管内皮细胞、星形胶质细胞和周细胞对辐射损伤的敏感性； 2)辐射所致脑血管细胞损伤与 抗氧化剂水平；3)确定生理刺激是否 一氧化氮生成增强放射性脑内皮细胞损伤 细胞，以确定阻断NO是否可以减轻这种损伤，以及 确定超氧阴离子在NO介导的损伤中可能起到的任何作用； 4)阐明基因修饰的分子机制。 内源性抗氧化系统(超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶) 或产生NO调节辐射诱导的细胞损伤程度； 以及，5)确定辐射损伤的水平是否 当细胞以混合培养方式生长时改变(内皮-周细胞和 内皮-星形胶质细胞)，以及是否对该反应进行了任何修饰 由于抗氧化剂在细胞间的转移，导致 产生抗氧化剂，或转移自由基，如NO。

Radiation therapy following surgery is the most effective treatment for malignant brain tumors, but clinically admissible radiation doses are limited because the radiation also damages normal tissue. If that damage could be ameliorated, radiation doses delivered to brain tumors might be increased and therapeutic efficacy enhanced. Radiation-induced brain damage often includes damage to the cerebral vasculature, as evidenced by prominent blood-brain barrier breakdown and cerebral edema. In this study, we wish to elucidate the mechanisms responsible for the sensitivity to radiation of the cells composing the cerebral vascular system. This work could suggest possible therapies directed toward ameliorating the radiation sensitivity of normal brain. We hypothesize that the differing endogenous levels of antioxidants, such as ascorbate, and pro-oxidants, such as the naturally occurring free radical nitric oxide (NO), are responsible for any differential radiosensitivity of cerebrovascular cells: and that modification of endogenous oxidant levels can modulate radiosensitivity. To test this hypothesis, we will examine the radiation sensitivity of primary cultures of cerebral endothelial cells, astrocytes, and pericytes from normal rats and mice and transgenic mice overexpressing human copper-zinc (CuZn)-superoxide dismutase (SOD) in the presence of various antioxidants and pro-oxidants. Our specific aims are: 1) to quantify the susceptibility of primary cell cultures of rat cerebral endothelial cells, astrocytes, and pericytes to radiation-induced injury; 2) to correlate radiation-induced injury to cerebrovascular cells with levels of antioxidants; 3) to determine whether physiologic stimulation of NO production enhances radiation-induced injury to cerebral endothelial cells, to determine whether blockage of NO can ameliorate such injury, and to establish any role the superoxide anion may have in NO-mediated damage; 4) to elucidate the molecular mechanism by which modification of endogenous antioxidant systems (SOD, catalase, and glutathione peroxidase) or production of NO modulate the degree of radiation-induced cell damage; and, 5) to determine whether the level of radiation-induced injury is altered when cells are grown as mixed cultures (endothelial-pericyte and endothelial-astrocyte), and whether any modification of the response is due to cell-to-cell transfer of antioxidants, to the induction of antioxidant production, or to transfer of free radicals such as NO.