RADIATION BIOLOGY OF SIMULATED RADON-DAUGHTER ALPHAS

总体描述（申请人的描述）该计划项目汇集并链接实验生物学中的四个项目，这些项目都涉及由α粒子刺激氡子体发射的α粒子引起的致癌机制的共同主题。美国国家科学院氡对健康影响BEIR VI委员会通过从地下矿井中明显的较高风险采用线性无阈值外推法，估计了家中氡导致肺癌的风险。这一决定主要是基于这样的结论，即单个α粒子可以在细胞核中产生足够的损伤，从而启动致癌过程。该计划项目质疑中心法则，即带电粒子通过细胞核是诱导生物系统的基本先决条件，终点将用于从损伤信号到染色体畸变，突变到致癌转化。要解决的问题包括：（1）带电粒子通过细胞质能否在细胞核中引起遗传效应？(2)通过跨核或跨胞质的α粒子横向传递到相邻细胞对一个细胞的损伤是否可以称为所谓的旁观者效应，介导该反应的机制是什么？(3)α粒子诱导的DNA断裂的空间和时间方面如何影响更复杂的生物损伤的诱导？(4)在被α粒子有机转化的细胞中，特定的基因是否一致地上调或下调，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?