Effect of Estrogen on Radiation-induced Cataractogenesis

描述(申请人提供)：白内障的诱发通常是头颈部或眼部肿瘤的常规放射治疗、全脑照射和自体骨髓移植前的全身照射的不幸和不可避免的后果。虽然不会危及生命，但辐射诱发的白内障是放射治疗的一种潜在的严重后遗症，需要手术干预。虽然辐射诱发白内障的细胞和分子机制(S)还不清楚，但辐射时对基因组的破坏以及晶状体上皮萌发区辐射敏感细胞的随后增殖可能在这一过程中发挥了作用。使用大鼠模型，我们最近积累了初步数据，表明雌激素缩短了潜伏期，并可能增加放射性白内障的发生率和严重程度。使用口服避孕药的非怀孕妇女或接受雌激素替代疗法的绝经后妇女人工诱导高雌激素水平，这些群体患上更严重或发病更快的白内障的风险可能会增加。雌激素调节多种参与细胞周期控制和细胞凋亡的蛋白质，其代谢导致自由基的产生，这些自由基可能对哺乳动物细胞具有遗传毒性和诱变作用。因此，在拟议的研究中要检验的一个新的假设是，雌激素改变了辐射后晶状体细胞的细胞周期调节、DNA双链断裂的诱导或修复以及增殖。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的作用机制，并将使用ERα或ERβ缺陷的基因敲除小鼠来确定雌激素对放射性白内障发生的调控是否由雌激素受体(ER)介导。晶状体经常被用作预测其他受辐射组织的延迟(迟发)效应的模型。从这项拟议的研究中获得的数据可能表明，晶状体是预测其他雌激素反应靶组织的晚期效应的有用模型。最后，还将测试利用一种新技术照射小动物的效果；在这项研究中，使用Leksell伽玛刀，每只动物只有一只眼睛被照射，对侧眼作为对照。

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.