GENOMIC INSTABILITY IN HIGH LET CARCINOGENESIS

描述：（申请人描述）

DESCRIPTION: (Applicant's Description) The objective of this research is to determine the role of radiation-induced genomic instability in radiation carcinogenesis. Previous studies have led the applicant to propose a model identifying genomic instability as the earliest cellular event in the multi-step sequence leading to radiation-induced cancer. To determine whether the induction of instability is mechanistically linked to cancer development requires information be obtained on induction maintenance, and propagation of genomic instability in vivo. Of particular relevance to this application are results demonstrating qualitative differences between effects of high and low LET radiations. If genomic in-stability is critical, it would be predicted that radiation quality should influence its degree and nature. These studies address several issues fundamental to testing the hypothesis and determining effects as a function of radiation quality. Specifically, the aims of this research are: 1) Determine the influence of cell environment on induction, persistence, and propagation of genomic instability as a function of radiation quality. Studies will examine induction of delayed instability by gamma rays, protons, neutrons and iron particles in mouse mammary epithelial cells irradiated in vitro and in vivo. Emphasis will be on the role of cell-cell interactions and cell proliferation. 2) Determine the impact of alterations in "critical" genes involved in cell cycle checkpoint control and apoptosis in radiation-induced instability. Studies will test whether genomic instability after high and low LET irradiation is associated with alterations in cell cycle check point control and the degree to which programmed cell death influences its propagation. 3) Characterize cellular processes involved in the development of radiation-induced instability. To test whether DNA repair mechanisms are involved in induction and propagation of instability, agents which influence repair processes will be used to modify development of instability post-irradiation. The in vivo/in vitro models provide an opportunity for detailed studies of radiation-induced genomic instability to test whether there is a mechanistic link between radiation-induced instability and carcinogenesis and whether there are differences as a function of radiation quality.