Mechanisms of radiation tolerance in Caenorhabditis from Chernobyl

切尔诺贝利秀丽隐杆线虫的辐射耐受机制

• 批准号: 10162588
• 负责人: Matthew Rockman
• 金额: $ 19.81万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-12 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162588
• 关键词: Accidents; Address; Affect; Air; Animals; Area; Background Radiation; Biological; Biological Assay; Biological Models; Caenorhabditis; Caenorhabditis elegans; Cesium; Chernobyl Nuclear Accident; Chronic; Cosmic Radiation; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA sequencing; Diagnosis; Disasters; Ecosystem; Elements; Environment; Environmental Risk Factor; Exclusion; Exposure to; Fertility; Fukushima; Generations; Genetic; Genetic Drift; Genetic Models; Genetic Predisposition to Disease; Genetic Variation; Genome; Grant; Health; Heritability; Human; Human Activities; Human Pathology; Inbreeding; Investigation; Ionizing radiation; Measurement; Measures; Medical; Microbe; Mutation; Nematoda; Nuclear; Nuclear Energy; Nuclear Fission; Nuclear Power Plants; Nuclear Weapons Testings; Organism; Pathologic; Pathway interactions; Population; Population Sizes; Power Plants; Radiation; Radiation Tolerance; Radiation exposure; Radioactive; Radioactive Waste; Recombinants; Research; Resolution; Risk; Sampling; Site; Strontium-90; Surveys; System; Taxon; Technology; Testing; Toxin; Travel; Ukraine; United States; Variant; Visit; Work; anthropogenesis; bioimaging; cancer therapy; coping; environmental radiation; experience; experimental study; human disease; life history; microbial; new technology; pressure; radiation response; repaired; response; soil sampling; space travel; trait

Many of the technological advances that increase our quality of living also increase our exposure to ionizing radiation, i.e. during medical diagnosis and treatment, nuclear weapons testing, power plant accidents, and air and space travel. Anthropogenic activity has nearly doubled the average background radiation (not including use in cancer therapy), while levels in some regions reach many orders of magnitude higher. Meanwhile, the effects of chronic exposure are poorly understood, including the levels at which nuclear contamination creates selective pressure on the ecosystem, and the unique pathological challenges of constant exposure. Microfauna from highly radioactive areas can help us understand these challenges, and suggest biomolecular remedies. The exploratory project we propose addresses the following three questions: (1) At what threshold does background radiation alter animal mutation rate? (2) Does a population's radiation tolerance depend on (a) avoidance of DNA damage, (b) optimization of DNA repair, or (c) increased fecundity and dispersal? And (3) which elements of DNA repair pathways are naturally variable, and what are the genetic and cellular signatures of the variants? To investigate these questions, we will travel to the Chernobyl Exclusion Zone in Ukraine and collect nematodes from areas with varying levels of contamination. Diverse genetic backgrounds and multiple decades of continuous exposure have likely enriched this region for organisms with high radiation tolerance. To identify how background radiation corresponds to mutational load, we will sequence the genomes of nematodes and microbes collected from each site, and evaluate local genetic divergence. To uncover the strategies used by animals that are successful in the presence of radiation, we will identify nematode strains that are genetically similar but diverge greatly in their sensitivity to multi-generational radiation exposure in the lab. By challenging these strains with radiation and comparing quantities of DNA breaks at various timepoints, we will determine whether the strains differ by protecting against, repairing, or coping with DNA breaks. Risk of human disease due to toxin exposure is often influenced by genetic predisposition. To investigate how heritable variations affect DNA damage repair and mutation rate, we will cross genetically similar sensitive and tolerant strains, and create a panel of recombinant inbred advanced intercross lines (RIAILS). By assaying these RIAILs' responses to DNA damage, we will elucidate which steps of the DNA repair pathways are variable, identify the genetic and cellular signatures of the variants, and measure how these variants optimize mutation rate in a radioactive environment. The work proposed here will utilize a historic environmental disaster and a genetically tractable organism to establish a model system for studying many facets of animal response to chronic radiation exposure. This model system will fuel research well beyond the timeframe of this grant, with direct implications for human pathologies caused by medical, environmental, and cosmic radiation exposure.

许多提高我们生活质量的技术进步也增加了我们对电离辐射的暴露。 辐射，即在医疗诊断和治疗、核武器试验、发电厂事故和空气中的辐射 和太空旅行。人类活动几乎使平均背景辐射增加了一倍（不包括 用于癌症治疗），而某些地区的水平则高出许多数量级。同时 长期暴露的影响知之甚少，包括核污染造成的水平。 对生态系统的选择性压力，以及持续暴露的独特病理挑战。微型动物 可以帮助我们理解这些挑战，并提出生物分子疗法。 我们提出的探索性项目解决了以下三个问题：（1）在什么阈值下， 背景辐射改变动物突变率？(2)人口的辐射耐受力是否取决于（a） 避免DNA损伤，（B）优化DNA修复，或（c）增加繁殖力和扩散？（3） DNA修复途径的哪些元素是自然可变的，遗传和细胞特征是什么？ 的变种？为了调查这些问题，我们将前往乌克兰的切尔诺贝利禁区， 从不同污染程度的地区收集线虫。不同的遗传背景和多种 几十年的持续照射可能使该区域富集了具有高辐射耐受性的生物。 为了确定背景辐射如何对应突变负荷，我们将对 线虫和微生物从每个网站收集，并评估当地的遗传分歧。将查清 策略所使用的动物是成功的存在下的辐射，我们将确定线虫菌株 这些基因相似，但在对多代辐射暴露的敏感性方面存在很大差异， 实验室通过用辐射攻击这些菌株并比较不同时间点的DNA断裂量， 我们将确定这些菌株是否通过保护、修复或应对DNA断裂而有所不同。 人类因接触毒素而患病的风险往往受到遗传易感性的影响。探讨如何 遗传变异影响DNA损伤修复和突变率，我们将交叉遗传相似的敏感和 耐受菌株，并创建一组重组近交高级互交系（RIAILS）。通过测定 这些RIAIL对DNA损伤的反应，我们将阐明DNA修复途径的哪些步骤是 变量，识别变异的遗传和细胞特征，并测量这些变异如何优化 在放射性环境中的突变率。 这里提出的工作将利用一个历史性的环境灾难和一个遗传上易处理的有机体， 建立一个模型系统，用于研究动物对慢性辐射照射的反应的许多方面。这 模型系统将推动研究远远超出了这一赠款的时间范围，对人类的直接影响 医疗、环境和宇宙辐射照射引起的病理学。