Probing the spatial and temporal evolution of DNA damage

$243,335P01FY2000CANIH

Columbia University Health Sciences, New York NY

Investigators

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Abstract

DESCRIPTION: (Applicant's Description) This project is formulated to address the fundamental question "why are alpha-particles more biologically damaging than x rays?" A mechanistic understanding of the effectiveness of alpha particles relative to x rays boils down to understanding spatial proximity effects, which is the central theme of this project. Both the spatial and temporal aspects of damage induction will be investigated. The microbeam, with its distinctive spatial specificity, is a unique tool which allows these phenomena to be probed quantitatively. The biological endpoints in this Project are chromosomal aberrations (inter-chromosomal and intra-chromosomal, [including inter-arm and intra-arm]). Comparable experiments will be undertaken in Projects 2, 3, and 4, with endpoints related to oncogenic transformation, mutation, and signal transduction, and will be subjected to similar analysis. Interaction probabilities as a function of distance will be studied, comparing the effects of pairs of alpha-particles delivered very close to one another (0.3 to 1.5 micron) with the effects of pairs of alpha-particles delivered at much larger separations. Interaction probabilities as a function of time will be studied, probing the motion of damaged chromatin, comparing the effects of two close-by alpha-particles delivered with the same spatial separation, but longer temporal separations (10 sec-1 hr). These experiments will also allow the possibility of recombinational misrepair to be addressed. This project also represents the "core" component of the grant for modeling and data analysis. The overall project is designed to address one of the central phenomena in radiation biology, namely the hierarchical progression of radiation damage from energy disposition, through damage signaling, mutational/chromosomal damage, and finally to survival and oncogenesis. Experimental design will be coordinated, and experimental results will be analyzed statistically using consistent, state-of-the-art techniques. Using these data, development will continue of consistent mechanistic models to stimulate the various steps in the hierarchical development of radiation damage.

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