Effect of Estrogen on Radiation-induced Cataractogenesis

雌激素对辐射诱发白内障发生的影响

• 批准号: 6600591
• 负责人: JOSEPH R DYNLACHT
• 金额: $ 14.74万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6600591
• 关键词: DNA damage; DNA repair; apoptosis; cataract; cell proliferation; estradiol; estrogen receptors; estrogens; flow cytometry; gene expression; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; laboratory rat; neoplasm /cancer radiation therapy; polymerase chain reaction; radiation sensitivity; radiation therapy dosage; radiobiology; western blottings; whole body irradiation effect

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.

描述（由申请人提供）：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之前的全身照射的不幸且不可避免的后果。 尽管不会危及生命，但辐射引起的白内障是放射治疗潜在的严重后遗症，可能需要手术干预。 虽然辐射诱发白内障发生的细胞和分子机制尚未明确阐明，但暴露时基因组的损伤以及随后晶状体上皮萌发区中辐射敏感细胞的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，表明雌激素会缩短潜伏期，并可能增加辐射引起的白内障的发病率和严重程度。 使用口服避孕药的非怀孕妇女或接受雌激素替代治疗的绝经后妇女人为诱发高雌激素水平，这些群体患白内障的风险可能更高，且白内障更严重或发病更快。 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，自由基可能对哺乳动物细胞具有遗传毒性和诱变性。因此，在拟议的研究中要测试的一个新假设是雌激素改变细胞周期调节、DNA 双链断裂诱导或修复以及受辐射晶状体细胞的增殖。 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机制，并且我们将使用缺乏 ERα 或 ERβ 的基因敲除小鼠来确定雌激素对放射性白内障发生的调节是否是雌激素受体（ER）介导的。 晶状体经常被用作预测其他受照射组织的延迟（晚期）效应的模型。从拟议的研究中获得的数据可能表明晶状体是预测其他雌激素反应性目标组织的迟发效应的有用模型。 最后，还应测试利用新技术照射小动物的效果；在本研究中，使用Leksell伽玛刀，每只动物只照射一只眼睛，以对侧眼睛作为对照。