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: 6923577
• 负责人: JOSEPH R DYNLACHT
• 金额: $ 14.55万
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6923577
• 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）：白内障的诱导通常是对头部和颈部或眼部肿瘤的常规放射疗法的不幸和不可避免的结果，在自体骨髓移植之前，全脑辐照以及全体辐照。 尽管没有威胁生命，但辐射诱导的白内迫切发生代表了放射疗法的潜在严重后遗症，可能需要手术干预。 虽然尚未明确阐明辐射诱导的白内迫切发生的细胞和分子机制，但在暴露时对基因组的损害以及随后在晶状体上皮发芽区的放射敏感细胞的增殖可能在此过程中起作用。 使用大鼠模型，我们最近积累了初步数据，该数据表明雌激素会降低潜在时期，并可能增加辐射诱导的白内障的发生率和严重程度。 使用口服避孕药或在雌激素后替代治疗的绝经后妇女中，非怀孕的女性人为地诱导高雌激素水平，这些组可能会增加患有更严重或更快发作的白内障的风险。 雌激素调节几种参与细胞周期控制和凋亡的蛋白质，其代谢导致自由基的产生，这些自由基可能是遗传毒性和诱变对哺乳动物细胞的产生。因此，在拟议的研究中要检验的一种新假设是，雌激素会改变细胞周期的调节，DNA双链断裂诱导或修复以及辐照透镜细胞中的增殖。 我们还将研究辐射和雌二醇的剂量时间相互作用，以更好地理解雌激素作用的机制，我们将确定使用使用Eralpha或Erbeta缺乏的基因敲除小鼠进行了雌激素受体（ER）介导的雌激素调节是雌激素受体（ER）介导的。 该镜头经常被用作预测其他辐照组织中延迟（晚）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靶向组织的迟到作用的有用模型。 最后，还应测试利用一种新技术进行小动物辐射的功效。在这项研究中，使用Leksell Gamma刀，每只动物中只能辐射一只眼睛，对侧眼对照。

项目成果

Estrogen protects against radiation-induced cataractogenesis.

• DOI: 10.1667/rr1416.1
• 发表时间: 2008-12
• 期刊: Radiation research
• 影响因子: 3.4
• 作者: Dynlacht JR;Valluri S;Lopez J;Greer F;Desrosiers C;Caperell-Grant A;Mendonca MS;Bigsby RM
• 通讯作者: Bigsby RM

Interstrain differences in the development of pyometra after estrogen treatment of rats.

雌激素治疗后大鼠子宫蓄脓发育的种间差异。

• 发表时间: 2009
• 期刊: Journal of the American Association for Laboratory Animal Science : JAALAS
• 作者: Brossia,LisaJane;Roberts,ChristopherSean;Lopez,JenniferT;Bigsby,RobertM;Dynlacht,JosephR
• 通讯作者: Dynlacht,JosephR