MOLECULAR GENETICS OF LUNG TUMOR PROMOTION IN MICE

摘要 利用不同品系的近交系小鼠进行的遗传连锁研究已经将肺 腺瘤易感性(PAS)和肺腺瘤耐药(PAR)基因座[1，2]。最近， 数量性状基因座(QTL)定位也确定了调节遗传的特定基因座 使用近亲繁殖的小鼠品系对肺部炎症的易感性[3]。有趣的是，常见的 染色体位置被发现同时调节肺部炎症和癌症的发生 提示肺部炎症在肺癌易感性中起因果作用[3]。我们 假设肺部炎症的遗传修饰物可以使用F2连锁来识别 在老鼠身上绘制地图，然后是精细的地图绘制策略。提出了四个具体目标来 完成我们的目标。在具体目标1中，我们将进行肺脏的遗传连锁图谱 暴露于肺刺激物丁基羟基甲苯(BHT)的小鼠炎症QTL。在……里面 与致癌物3-甲基胆蒽(MCA)结合，BHT可促进MCA诱导的肺损伤 肿瘤发生学。我们建议使用两个品系的小鼠(BALB/cByJ和BALB/cByJ)的F2后代 C57BL6/J)，具有极端炎症和炎症诱导的肿瘤促进表型。在……里面 目标2，我们将进行单倍型和全基因组连锁不平衡分析，以指导 发现新的QTL，并在目标3中指导和告知目标基因座。我们最近 论证了关联分析在玉米品种精细定位和鉴定中的可行性 肺腺癌的候选易感基因[4]。目标3将对主要QTL进行精细定位 与肺部炎症和肿瘤促进的遗传易感性有关 炎症易感等位基因替代的同源小鼠品系的建立 抗炎小鼠的遗传背景。QTL将通过以下方式精细定位 通过生产亚基因小鼠品系逐步减少QTL区域以 把它缩小到0.5-1厘米左右。目的4通过定位确定候选基因(S) 克隆。精细作图区域的DNA序列将通过比较 完整的小鼠基因组数据库。候选基因将根据已识别的基因进行识别 两个亲本品系小鼠的功能多态性及其表达差异 在疾病发展的不同阶段。这些研究的意义在于，它们将 确定可能与肺部炎症易感基因有关的候选基因 人类对肺癌的遗传易感性。

ABSTRACT Genetic linkage studies using various strains of inbred mice have mapped pulmonary adenoma susceptibility (Pas) and pulmonary adenoma resistance (Par) loci [1,2]. Recently, quantitative trait locus (QTL) mapping also identified specific loci that regulate genetic susceptibility to pulmonary inflammation using inbred mouse strains [3]. Interestingly, common chromosomal locations were found to regulate both pulmonary inflammation and carcinogenesis suggesting a causal role of pulmonary inflammation in lung tumor susceptibility [3]. We hypothesize that genetic modifiers of pulmonary inflammation can be identified using F2 linkage mapping in mice followed by fine mapping strategies. Four specific aims are proposed to accomplish our goal. In Specific Aim 1, we will conduct genetic linkage mapping of pulmonary inflammation QTL in mice exposed to the lung irritant, butylated hydroxytoluene (BHT). In combination with the carcinogen 3-methylcholanthrene (MCA), BHT promotes MCA-induced lung tumorigenesis. We propose to use the F2 progeny of two strains of mice (BALB/cByJ and C57BL6/J) with extreme inflammation and inflammation-induced tumor promotion phenotypes. In Aim 2, we will conduct haplotype and whole-genome linkage disequilibrium analyses to guide discover new QTLs and guide and inform which loci to target in Aim 3. We have recently demonstrated the feasibility of association analysis in the fine mapping and identification of candidate susceptibility genes for lung adenocarcinomas [4]. Aim 3 will fine map the major QTL related to genetic susceptibility to pulmonary inflammation and tumor promotion by the production of congenic strains of mice in which the inflammation susceptible allele is substituted onto the genetic background of the inflammation resistant mice. The QTL will be fine-mapped by progressively reducing the QTL region through the production of sub-congenic mouse strains to narrow it to a size of around 0.5-1 cM. Aim 4 will identify the candidate gene(s) by positional cloning. DNA sequences of the fine mapped region will be obtained through comparison of completed mouse genomic databases. Candidate genes will be identified based on identified functional polymorphisms and differences in expression between the two parental strains of mice at different stages of disease progression. The significance of these studies is that they will identify candidate pulmonary inflammation susceptibility genes that may also contribute to genetic susceptibility to lung cancer in humans.