IDENTIFICATION OF TUMOR PROMOTION SUSCEPTIBILITY GENES

拟议研究的主要目的是绘制和识别

The primary aim of the proposed research is to map and identify genes that regulate responsiveness to skin tumor promotion in mice. Current evidence indicates that tumor promotion plays an important role in the etiology of human cancer emphasizing the importance of studies related to this process. It is clear from a number of investigations that dramatic variation in response to epidermal carcinogenesis exists between various mouse stocks and strains. Earlier work from Dr. DiGiovanni's laboratory, as well as others, has shown that susceptibility to the tumor promotion stage is a major determinant of overall susceptibility to epidermal carcinogenesis in mice. Additional studies from Dr. DiGiovanni's laboratory have shown that genetic control of susceptibility to tumor promotion by the phorbol ester TPA in crosses between DBA/2 and C57B1/6 mice involves a minimum of three genes. Furthermore, he has now obtained genetic data from BxD recombinant inbred mice and from B6D2F1xC57B1/6 backcross and B6D2F2 mice (all previously tested for susceptibility to TPA promotion) using microsatellite markers, that sugggest a strong association of TPA promotion susceptibility with a region on chromosome 9 (LOD score of 3.8). The identification of one or more promotion susceptibility gene(s) will greatly increase knowledge of the process of tumor promotion in mouse skin and tumor promotion in general and my ultimately lead to the identification of genes in human populations that regulate susceptibility to tumor promoting stimuli. The hypothesis to be tested in the proposed research is that a distinct gene exists on chromosome 9 that is associated with responsiveness to TPA-induced skin tumor promotion in DBA/2 mice. The specific Aims are: 1) to fine map the putative TPA promotion susceptibility locus on chromosome 9 (including the construction of a set of congenic lines between DBA/2 and C57B1/6 mice to aid in fine mapping); 2) To analyze potential candidate tumor promoting susceptibility genes that map to the minimal region on chromosome 9; 3) To clone and characterize the putative TPA promoting susceptibility gene on chromosome 9; 4) To use congenic lines to address mechanistic questions regarding the putative TPA promotion susceptibility locus on chromosome 9; and 5) to continue searching for other tumor promotion susceptibility and/or resistance genes.