Positionaing Cloning of Lung Cancer Modifier Gene Par2

描述（由申请方提供）：本提案的目的是鉴定Par 2基因，该基因负责BALB/cByJ小鼠肺肿瘤对化学致癌物的耐药性。虽然肺癌在很大程度上与吸烟有关，但有强有力的证据表明肺癌的发生与遗传易感性和基因-环境相互作用有关。近交系小鼠模型提供了一种有效的手段，确定候选人肺癌改性剂，因为遗传异质性和巨大的变化，暴露水平的环境因素，使其难以确定肺癌易感基因座在人类。一个主要的数量性状基因座（QTL）位点命名为肺腺瘤抗性基因2（Par 2）负责50%的变异之间的肿瘤多样性的A/J小鼠和BALB/cByJ小鼠已被定位到小鼠染色体18。QTL定位结果已被证实的同源株的生产，其中高肺肿瘤易感性（A/J）等位基因被替换到BALB/cJ小鼠的遗传背景。在这个提议中，我们将通过生产亚同源小鼠品系逐步减少QTL区域，将其缩小到约0.2-0.5 cM的大小，从而精细定位Par 2 QTL。整个缩小区域的DNA序列将通过完整的小鼠基因组数据库获得。将鉴定靶区域中的新的和已知的基因，并基于已知或推导的功能和/或A/J小鼠和BALB/cJ小鼠之间的表达差异寻找候选基因。然后通过构建具有A/J Par 2等位基因替换BALB/cJ等位基因的敲入小鼠来评估候选Par 2基因的功能作用。将对所得小鼠进行肺癌发生试验以确认Par 2基因。由于Par 2已被证明是Pas 1 QTL的负修饰子，我们将产生在Pas 1基因座存在或不存在的情况下含有Par 2基因座的双同源菌株。双基因组和单基因组之间肺肿瘤反应的比较将允许定义所涉及的基因座之间的相互作用。这些研究的意义在于，它们将确定Par 2基因，其人类同源物可能使某些个体易患肺癌。

DESCRIPTION (provided by applicant): The goal of this proposal is to identify the Par2 gene, which is responsible for lung tumor resistance in the BALB/cByJ mouse to chemical carcinogens. Although lung cancer is largely associated with smoking, there is strong evidence for genetic susceptibility and gene-environment interactions in the development of lung cancer. Inbred mouse models offer an effective means of identifying candidate lung cancer modifiers since genetic heterogeneity and enormous variation in exposure levels to environmental agents makes it difficult to identify lung cancer susceptibility loci in humans. A major quantitative trait loci (QTL) locus named pulmonary adenoma resistance gene 2 (Par2) responsible for 50% of variance in tumor multiplicity between the A/J mouse and the BALB/cByJ mouse has been mapped to mouse chromosomes 18. The QTL mapping result has been confirmed by the production of congenic strains in which high lung tumor susceptibility (A/J) allele was substituted onto the genetic background of the BALB/cJ mouse. In this proposal, we will fine map the Par2 QTL by progressively reducing the QTL region through the production of subcongenic mouse strains to narrow it to a size of around 0.2-0.5 cM. DNA sequences of the entire narrowed region will be obtained through completed mouse genomic databases. New and known genes in the target region will be identified and candidate genes will be sought based on known or deduced function and/or differences in expression between A/J mice and BALB/cJ mice. The functional role of the candidate Par2 gene will then be evaluated by constructing knock-in mice with the A/J Par2 allele replacing the BALB/cJ allele. The resulting mouse will be subjected to lung carcinogenesis assay to confirm the Par2 gene. Since the Par2 has been shown to be a negative modifier of the Pas1 QTL, we will produce double congenic strains that contain the Par2 locus in the presence or absence of the Pas1 locus. Comparisons of lung tumor response among double and single congenics will allow definition of interactions between the loci involved. The significance of these studies is that they will identify the Par2 gene whose human homologue may predispose some individuals to lung cancer.