The long term objective of this proposal is to gain a better understanding of factors governing cellular responses to ionizing radiation as they bear on dose rate and dose fractionation effects of interest for radiation oncology and issues of low level radiation hazards to humans. Repair processes, the intrinsic sensitivity of cells, and their proliferative status are factors which would be studied. There are two general aims. The first is to study dose-time effect in relation to the proliferative status of cells. Specifically, we would (1) measure dose response and dose rate effects for delays in the transition from the noncycling to cycling state of normal human cells in culture; (2) map the G0/G1 x-ray transition delay point with respect to sequential biochemical events known to accompany the transition, and (3) develop a DNA polymerase alpha monoclonal antibody staining technique to determine """"""""growth fraction"""""""" in dog tumors and possible changes ingrowth fraction and the proportion of cycling cells in some normal tissues during radiotherapy. The second general aim is to continue studies on the genetic control of cellular responses to radiation and hyperphermia. Specifically, this would involve (4) continuing attempts to isolate and characterize x-ray sensitive mutants of OHO cells; (5) isolation"""""""" and characteristion of additional CHO mutants that are deffective in their ability to develop thermotolerance; (6) carry but complementation analyses is cell hybrids among mutants isolated in (4) and (5) above; (7) map genes controlling radiation and heat sensitivity with respect to their location on human chromosomes in CHO/human hybrids and (8) isolate mutants deficient in (a) DNA Polymerase beta and (b) glutathione or glutathione transferase to assess the role of these in modulating cellular responses to free radical generating agents.
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