IDENTIFICATION OF TUMOR PROMOTION SUSCEPTIBILITY GENES

拟议研究的主要目的是绘制和识别 调节小鼠皮肤肿瘤促进反应的基因。 目前的证据表明，肿瘤的促进作用是重要的， 在人类癌症病因学中的作用， 与这个过程有关的研究。 从许多方面来看， 研究表明，对表皮细胞的反应 在各种小鼠种群和品系之间存在致癌作用。 迪乔瓦尼博士的实验室以及其他人的早期工作， 显示对肿瘤促进阶段易感性是主要的 表皮癌发生总体易感性的决定因素 小鼠 迪乔瓦尼博士实验室的进一步研究表明， 基因控制肿瘤的易感性， 佛波醇酯TPA在DBA/2和C57 B1/6小鼠间的杂交中 至少包含三个基因 此外，他现在 从BxD重组近交系小鼠和从 B6 D2 F1 xC 57 B1/6回交和B6 D2 F2小鼠（所有先前检测 对于TPA促进的易感性）使用微卫星标记， 证实TPA促进易感性与 9号染色体上的区域（LOD评分为3.8）。 的识别 一个或多个促进易感性基因将大大增加 小鼠皮肤中肿瘤促进过程的知识， 肿瘤的一般促进和我最终导致 在人群中鉴定调节易感性的基因 肿瘤促进刺激。 要检验的假设是 一项研究表明，9号染色体上存在一种独特的基因， 与TPA诱导的皮肤肿瘤的反应性有关 在DBA/2小鼠中促进。 具体目标是：1）精细映射 9号染色体上的假定TPA促进易感性位点 （包括DBA/2和DBA/2之间同源系的构建） 和C57 B1/6小鼠以帮助精细定位）; 2）分析潜在的 候选肿瘤促进易感基因，映射到 9号染色体上的最小区域; 3）克隆和表征 9号染色体上的推定TPA促进易感基因; 4） 使用同类系来解决关于 9号染色体上的推定TPA促进易感性基因座;和5） 继续寻找其他肿瘤促进易感性和/或 抗性基因

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.