Biological mechanisms of the ionizing radiation response in lens epithelial cells

晶状体上皮细胞电离辐射反应的生物学机制

• 批准号: RGPIN-2019-06583
• 负责人: Thome, Christopher
• 金额: $ 2.04万
• 依托单位: Laurentian University of Sudbury
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760904
• 关键词: Biological; mechanisms; ionizing; radiation; response

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.

该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、基因突变和致癌作用的增加，这在高剂量急性照射后已得到充分证明。然而，关于低剂量区域辐射照射的生物影响仍有争议。越来越多的证据表明，生命系统对低剂量辐射的反应不同，目前的许多风险模型支持阈值或激素关系。我过去的工作已经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。这项具体建议的短期目标是调查眼睛透镜对电离辐射照射的生物反应。哺乳动物的透镜被认为是最敏感的放射组织之一。然而，最近有关于剂量率在透镜损伤中所起的作用以及是否存在放射性效应的阈值剂量的争论。拟议的研究将调查这些基本问题，通过研究在培养的透镜上皮细胞（LEC）的X射线照射的机制。在第一个目标中，将在几种急性和长期剂量率下比较氧化应激和基因组损伤的剂量反应。接下来，将研究由辐射诱导的基因组损伤引起的细胞增殖的功能变化和改变。最后，我们将确定转录和蛋白质的变化参与低剂量辐射反应。这个初步的建议将集中在培养LEC的细胞和分子的变化。后续研究将纳入动物模型，以确认观察到的对体内透镜的放射性影响。这一正在进行的低剂量放射生物学研究计划的结果将促进我们对电离辐射引起的遗传毒性损伤和氧化应激的细胞反应的理解。从这一具体建议中产生的数据将有助于填补我们对眼睛透镜辐射暴露机制的理解中的关键空白。由于已知透镜具有辐射敏感性，因此其可用作其他组织辐射损伤的生物指示剂。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暴露在自然背景源中的东西，生物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的使用越来越多，阐明辐射的影响至关重要。