Biological mechanisms of the ionizing radiation response in lens epithelial cells

这项研究计划的长期目标是调查低剂量辐射生物反应背后的机制。电离辐射可导致氧化应激、基因突变和致癌增加，这已在高剂量急性暴露后得到很好的证明。然而，关于低剂量辐射暴露的生物学影响，仍然存在争议。越来越多的证据表明，生命系统对低剂量辐射的反应是不同的，许多目前的风险模型支持阈值或兴奋关系。我过去的工作探索了低剂量和低剂量率辐射的几个方面，这些主题将继续在我正在建立的放射生物学研究计划中进行研究。 这项具体提案的短期目标是调查眼睛晶状体中电离辐射暴露的生物反应。哺乳动物的晶状体被认为是对辐射最敏感的组织之一。然而，最近关于剂量率在晶状体损伤中所起的作用以及是否存在辐射致辐射效应的阈值剂量存在争议。这项拟议的研究将通过研究X-射线照射培养的晶状体上皮细胞(LEC)的机制来探讨这些基本问题。在第一个目标中，将比较几种急性和长期剂量率对氧化应激和基因组损伤的剂量反应。接下来，将研究这种辐射诱导的基因组损伤导致的功能变化和细胞增殖的变化。最后，我们将确定低剂量辐射反应中涉及的转录本和蛋白质的变化。这项初步建议将重点放在培养的LEC的细胞和分子变化上。后续研究将纳入动物模型，以验证观察到的体内晶状体的辐射效应。 这项正在进行的低剂量放射生物学研究项目的结果将促进我们对细胞对电离辐射引起的遗传毒性损伤和氧化应激的反应的理解。这一具体建议产生的数据将有助于填补我们对眼睛晶状体辐射暴露机制的理解方面的关键空白。由于众所周知，晶状体对辐射敏感，它可以作为辐射对其他组织损害的生物指示器。此外，这项研究将有助于回答有关剂量率的作用和辐射阈值的存在的基本问题。电离辐射是所有生物系统每天都会从自然本底来源暴露到的东西，有机体已经适应了这种低水平的压力。随着辐射在医疗诊断、治疗程序和职业实践中越来越多地使用，阐明辐射的影响至关重要。

The long-term goals of this research program are to investigate the mechanisms behind the biological response to low dose radiation. Ionizing radiation can result in an increase in oxidative stress, genetic mutations and carcinogenesis, and this has been well documented following high dose acute exposures. However, there is still debate regarding the biological implications of radiation exposure in the low dose region. There is growing evidence that living systems respond differently to low dose radiation and many current models of risk support a threshold or hormetic relationship. My past work has explored several aspects of low dose and low dose rate radiation, and these topics will continue to be investigated in the research program in radiobiology that I am establishing. The short-term goals of this specific proposal are to investigate the biological response to ionizing radiation exposure in the lens of the eye. The mammalian lens is believed to be one of the most radiosensitive tissues. However, there has recently been debate regarding the role that dose rate plays in lens damage and whether there is a threshold dose for radiogenic effects. The proposed research will investigate these fundamental questions by studying the mechanism of x-radiation exposure in cultured lens epithelial cells (LEC). In the first aim, the dose response for oxidative stress and genomic damage will be compared across several acute and protracted dose rates. Next, functional changes and alterations in cell proliferation resulting from this radiation-induced genomic damage will be investigated. Finally, we will identify transcript and protein changes involved in the low dose radiation response. This initial proposal will focus on cellular and molecular changes in cultured LEC. Follow up studies will incorporate animal models to validate the observed radiogenic effects on the lens in-vivo. The results of this ongoing research program in low dose radiobiology will advance our understanding of the cellular response to genotoxic damage and oxidative stress induced by ionizing radiation. The data generated from this specific proposal will help to fill in critical gaps in our understanding of the mechanism of radiation exposure to the lens of the eye. As the lens is known to be radiosensitive, it can serve as a bioindicator for radiation damage to other tissues. In addition, this research will help to answer fundamental questions regarding the role of dose rate and the presence of radiation thresholds. Ionizing radiation is something that all biological systems are exposed to on a daily basis from natural background sources and organisms have adapted to living with this low level stress. Elucidating the effects of radiation is essential with its growing use in medical diagnostics, therapeutic procedures and occupational practices.