Effect of Estrogen on Radiation-induced Cataractogenesis

描述（由申请人提供）：白内障的诱导通常是在自体骨髓移植之前对头颈部或眼部肿瘤进行常规放射治疗、全脑照射和全身照射的不幸和不可避免的后果。 辐射诱发的白内障虽然不会危及生命，但可能是放射治疗的严重后遗症，需要手术干预。 虽然辐射诱导的白内障形成的细胞和分子机制尚未明确阐明，但在照射时基因组的损伤和随后透镜上皮细胞生发区中辐射敏感细胞的增殖可能在该过程中发挥作用。 我们最近利用大鼠模型积累的初步数据表明，雌激素缩短了潜伏期，并可能增加辐射诱发白内障的发病率和严重程度。 在使用口服避孕药的非妊娠妇女或接受雌激素替代疗法的绝经后妇女中，人为诱导高雌激素水平，这些群体可能会增加患白内障的风险，这些白内障更严重或发病更快。 雌激素调节参与细胞周期控制和凋亡的几种蛋白质，其代谢导致产生对哺乳动物细胞可能具有遗传毒性和致突变性的自由基。因此，一个新的假设，以测试在拟议的研究是，雌激素改变细胞周期的调节，DNA双链断裂的诱导或修复，并在照射透镜细胞的增殖。 我们还将研究辐射和雌二醇的剂量-时间相互作用，以更好地了解雌激素作用的机制，我们将使用ER α或ER β缺陷的基因敲除小鼠确定雌激素对辐射性白内障发生的调节是否是雌激素受体（ER）介导的。 透镜经常被用作预测其他辐照组织中延迟（晚期）效应的模型。从拟议的研究中获得的数据可能表明，透镜是一个有用的模型，用于预测在其他雌激素反应的靶组织的晚期效应。 最后，还应测试使用新技术进行小动物辐照的有效性;在本研究中，使用Leksell伽玛刀，每只动物仅对一只眼睛进行辐照，对侧眼睛作为对照。

DESCRIPTION (provided by applicant): The induction of cataracts is often an unfortunate and unavoidable consequence of conventional radiation therapy for head and neck or ocular tumors, whole-brain irradiation, and total-body irradiation prior to autologous bone marrow transplantation. Though not life-threatening, radiation-induced cataractogenesis represents a potentially serious sequelae of radiotherapy which can require surgical intervention. While the cellular and molecular mechanism(s) of radiation-induced cataractogenesis have not been clearly elucidated, damage to the genome at the time of exposure and subsequent proliferation of the radiosensitive cells in the germinative zone of the lens epithelium likely play a role in the process. Using a rat model, we have recently accumulated preliminary data which indicate that estrogen reduces the latent period and may increase the incidence and severity of radiation-induced cataracts. High estrogen levels are artificially induced in nonpregnant women using oral contraceptives, or in post-menopausal women on estrogen replacement therapy, and these groups may be at an increased risk for developing cataracts which are more severe or occur with a more rapid onset. Estrogens regulate several proteins involved in cell cycle control and apoptosis, and its metabolism results in the production of free radicals which may be genotoxic and mutagenic to mammalian cells. Thus, a novel hypothesis to be tested in the proposed studies is that estrogen alters cell cycle regulation, DNA double strand break induction or repair, and proliferation in irradiated lens cells. We shall also investigate the dose-time interactions of radiation and estradiol to better understand the mechanism of estrogen action, and we will determine whether estrogen-modulation of radiation cataractogenesis is estrogen receptor (ER)-mediated using knockout mice that are deficient in either ERalpha or ERbeta. The lens has frequently been used as a model for predicting delayed (late) effects in other irradiated tissues. Data obtained from the proposed study may demonstrate that the lens is a useful model for predicting late effects in other estrogen-responsive target tissues. Finally, the efficacy of utilizing a novel technique for small animal irradiations shall also be tested; in this study, using the Leksell Gamma Knife, only one eye shall be irradiated in each of the animals, with the contralateral eye serving as a control.