CYTOGENETIC MODELS FOR ASSESSING LOW DOSE RADIATION RISK

用于评估低剂量辐射风险的细胞遗传学模型

• 批准号: 6175032
• 负责人: RAINER K SACHS
• 金额: $ 21.97万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6175032
• 关键词: cancer risk; chromosome aberrations; computer simulation; cytogenetics; gamma radiation; genetic crossing over; genetic models; human genetic material tag; in situ hybridization; mathematical model; model design /development; radiation carcinogen; radiation carcinogenesis; radiation dosage; radiation genetics; radiation related neoplasm /cancer

Science-based assessments of environmental or occupational cancer risks from sparsely ionizing radiation estimate effects on large populations from doses that are very small compared to typical experimental doses and small compared even to epidemiologically tractable doses. A priority is developing credible dose-response relationships, both in an intermediate-dose range (up to 2 Gy or more) where epidemiology is feasible and in the most relevant, low-dose range (<0.1 Gy). The pertinent initial damage, such as DNA double strand breaks, is almost certainly produced linearly with dose, so the main issue is cellular processing of initial damage, via molecular repair/misrepair pathways, which can result in more complex endpoints such as chromosome aberrations and, ultimately, cancer. Exchange-type chromosome aberrations, produced during the GOIGl cell cycle phase and scored at the next metaphase, are complex endpoints, characteristic of ionizing radiation damage and highly relevant to carcinogenesis risk estimation. The goal of our project is using in vitro experiments on human cells and quantitative, mechanistic modeling to find realistic dose- response relations for such aberrations in a dose range from 0.08-2 Gy, as a practical surrogate for studying carcinogenesis in vivo at low doses. Biophysical and Monte Carlo computer analysis, comparing the best currently available models of molecular aberration formation pathways to data is emphasized as a relatively inexpensive approach. We have assembled a team of modelers and experimental radiobiologists from UC Berkeley, Columbia, and Harvard for the project. Exchange-type chromosome aberrations will be measured with state-of-the-art fluorescent in situ hybridization techniques after y-irradiation of human lymphocytes. Modeling will use extensions of sophisticated CAS (chromosome aberration simulator) computer software previously written and successfully applied by members of our team. The main novelties in the proposal are: close integration of mechanistic computer modeling with low-dose experiments; using repeated low-dose fractions to enhance response above background; including inversions and complex aberrations among the aberrations measured for risk-estimation purposes; and explicit consideration of the recombination-repair aberration formation model. By studying molecular, mechanisms relevant to low doses and low dose-rates quantitatively the project will help firm-up risk estimates and make them more credible.

对稀疏电离辐射造成的环境或职业癌症风险进行基于科学的评估，估计与典型实验剂量相比非常小的剂量对大量人群的影响，甚至与流行病学上易于处理的剂量相比也很小。优先事项是建立可靠的剂量反应关系，无论是在流行病学可行的中等剂量范围（高达 2 Gy 或更高），还是在最相关的低剂量范围（<0.1 Gy）。相关的初始损伤，例如 DNA 双链断裂，几乎肯定是与剂量呈线性关系产生的，因此主要问题是通过分子修复/误修复途径对初始损伤的细胞处理，这可能导致更复杂的终点，例如染色体畸变，并最终导致癌症。在GOIG1细胞周期阶段产生并在下一个中期评分的交换型染色体畸变是复杂的终点、电离辐射损伤的特征并且与癌发生风险评估高度相关。我们项目的目标是利用人体细胞体外实验和定量机制模型来寻找 0.08-2 Gy 剂量范围内此类畸变的真实剂量反应关系，作为研究低剂量体内致癌作用的实用替代品。生物物理和蒙特卡罗计算机分析，将当前可用的分子畸变形成途径的最佳模型与数据进行比较，被强调为一种相对便宜的方法。我们为该项目组建了一支由来自加州大学伯克利分校、哥伦比亚大学和哈佛大学的建模师和实验放射生物学家组成的团队。对人类淋巴细胞进行γ射线照射后，将使用最先进的荧光原位杂交技术来测量交换型染色体畸变。建模将使用我们团队成员之前编写并成功应用的复杂 CAS（染色体畸变模拟器）计算机软件的扩展。该提案的主要新颖之处在于：机械计算机建模与低剂量实验的紧密结合；使用重复的低剂量分数来增强高于背景的反应；包括出于风险评估目的而测量的像差中的倒置和复杂像差；并明确考虑重组修复像差形成模型。通过定量研究与低剂量和低剂量率相关的分子机制，该项目将有助于加强风险评估并使其更加可信。