(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?
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