Radiation Biology of Simulated Radon-Daughter Alphas

总体描述(申请人的描述)本计划项目汇集并连接了实验生物学中的四个项目，这些项目都解决了阿尔法粒子诱发致癌机制的共同主题，这些阿尔法粒子刺激了氡子体释放的粒子。美国国家科学院关于氡对健康影响的Beir VI委员会通过采用线性无阈值外推方法，从地下矿山明显存在的较高风险出发，估计了家庭中氡造成的肺癌风险。这一决定在很大程度上是基于这样一个结论，即单一的阿尔法粒子可以在细胞核中产生足够的损害，从而启动致癌过程。这个计划项目质疑中心教条，即带电粒子通过原子核是诱导生物系统的必要先决条件，端点将用于从损伤信号到染色体异常，从突变到致癌转化。有待解决的问题包括：(1)带电粒子穿过细胞质是否会在细胞核内引起遗传效应？(2)跨核或跨细胞质的α粒子横穿是否会损害一个细胞，即所谓的旁观者效应？其机制是什么(S)？(3)α粒子诱导的DNA断裂的时空方面如何影响更复杂的生物损伤的诱导？(4)在由α粒子有机转化的细胞中，特定基因是持续上调还是下调，转化的发生率是否被特定基因的激活所改变？

OVERALL DESCRIPTION (Applicant's Description) This program project brings together and links four projects in experimental biology that all address the common theme of the mechanisms of carcinogenesis induced by alpha-particles that stimulate those emitted by radon progeny. The BEIR VI Committee of the National Academy of Sciences on the Health Effects of Radon estimated lung cancer risks from radon in homes by adopting a linear no-threshold extrapolation from the higher risks evident in underground mines. This decision was based largely on the conclusion that a single alpha-particle could produce sufficient damage in a cell nucleus to initiate the carcinogenic process. This program project questions the central dogma that the passage of a charged particle through the nucleus is an essential pre-requisite for the induction of biological systems and endpoints will be used from damage signals to chromosomal aberrations, to mutations to oncogenic transformation. The questions to be addressed include: (1) Can the passage of a charged particle through the cytoplasm cause heritable effects in the nucleus? (2) Can damage to one cell by trans-nuclear or trans-cytoplasmic, alpha- particle transversals by transmitted to neighboring cells the so-called bystander effect and what are the mechanism(s) mediating the response? (3) How do the spatial and temporal aspects of alpha-particle induced DNA breaks affect the induction of more complex biological damage? (4) Are specific genes consistently up-regulated or down-regulated in cells organically transformed by alpha-particles, and is the incidence of transformation modified by the activation of specific genes?