MOLECULAR GENETICS OF LUNG TUMOR PROMOTION IN MICE

小鼠肺肿瘤促进的分子遗传学

• 批准号: 7736100
• 负责人: Pengyuan Liu
• 金额: $ 31.54万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-10 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736100
• 关键词: 3-Methylcholanthrene; Alleles; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; BALB/cByJ Mouse; Biological Markers; Budesonide; Butylated Hydroxytoluene; Candidate Disease Gene; Carcinogens; Chromosome Mapping; Chronic; Chronic Obstructive Airway Disease; Clinical; Cloning; Congenic Mice; Congenic Strain; Development; Disease Progression; Gene Expression; Gene-Modified; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genome; Goals; Haplotypes; Human; Inbred Strains Mice; Indomethacin; Inflammation; Inflammatory; Irritants; Link; Linkage Disequilibrium; Linkage Disequilibrium Mapping; Location; Lung; Lung Adenocarcinoma; Lung Adenoma; Lung Inflammation; Lung Neoplasms; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Molecular Genetics; Mouse Strains; Mus; Patients; Pattern; Penetrance; Phenotype; Play; Pneumonia; Predisposition; Process; Production; Quantitative Trait Loci; Reporting; Resistance; Role; Staging; Structure; Susceptibility Gene; Tumor Promotion; Variant; base; cancer risk; candidate identification; carcinogenesis; epidemiologic data; genetic linkage; genome-wide linkage; lung tumorigenesis; positional cloning; public health relevance

DESCRIPTION (provided by applicant): 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 and linkage disequilibrium (LD) 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 to map QTLs. In Aim 2, we will conduct haplotype and whole-genome LD analyses to 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. Candidate genes will be identified based on identified functional polymorphisms and differences in gene 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. PUBLIC HEALTH RELEVANCE: Increasing evidence supports a direct link between inflammation and cancer, and lung cancer in particular. Epidemiologic data in humans have shown an increased cancer risk in patients with various inflammatory diseases of the lung, including chronic obstructive pulmonary disease (COPD) and asthma, among others. Inflammation was found to enhance the development of lung tumors in mice. Many of the QTLs that control genetic susceptibility to lung inflammation, also co-localize with QTLs that regulate lung tumor susceptibility in mice. Administration of budesonide and indomethacin (with anti-inflammatory activity) inhibit lung tumorigenesis in mice and inflammation biomarkers including Cox1 and Cox2 are frequently elevated in both mouse and human lung cancers. These associations between inflammation and lung cancer suggest that pulmonary inflammation appears to be a key tumor promotion step during the lung tumorigenesis process. The objective of this proposal is to identify genetic modifiers of pulmonary inflammation. 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.

描述（由申请人提供）：使用不同品系的近交系小鼠进行的遗传连锁研究绘制了肺腺瘤易感性（Pas）和肺腺瘤抗性（Par）基因座1，2。最近，数量性状基因座（QTL）定位也确定了特定的基因座，调节遗传易感性肺部炎症使用近交系小鼠品系3。有趣的是，发现共同的染色体位置调节肺部炎症和癌变，表明肺部炎症在肺部肿瘤易感性中的因果作用3。我们假设肺部炎症的遗传修饰因子可以通过小鼠F2连锁和连锁不平衡（LD）定位以及精细定位策略来识别。为实现这一目标，提出了四个具体目标。在具体目标1中，我们将在暴露于肺刺激物二丁基羟基甲苯（BHT）的小鼠中进行肺部炎症QTL的遗传连锁作图。BHT与致癌物3-甲基胆蒽（MCA）联合使用时，可促进MCA诱导的肺肿瘤发生。我们建议使用两个品系的小鼠（BALB/cByJ和C57 BL 6/J）的F2后代与极端炎症和炎症诱导的肿瘤促进表型定位QTL。在目标2中，我们将进行单倍型和全基因组LD分析，以发现新的QTL，并指导和告知目标3中靶向的位点。我们最近证明了关联分析在肺腺癌候选易感基因的精细定位和鉴定中的可行性4。目的3通过将炎症易感等位基因替换到炎症抵抗小鼠的遗传背景上，产生小鼠的同类系，精细定位与肺部炎症和肿瘤促进的遗传易感性相关的主要QTL。QTL将通过产生亚同源小鼠品系逐渐减少QTL区域以将其缩小到约0.5-1 cM的大小来精细定位。目的4将通过定位克隆来鉴定候选基因。候选基因将基于在疾病进展的不同阶段的两个亲本小鼠品系之间鉴定的功能多态性和基因表达的差异来鉴定。这些研究的意义在于，它们将确定可能也有助于人类肺癌遗传易感性的候选肺部炎症易感基因。公共卫生相关性：越来越多的证据支持炎症和癌症之间的直接联系，特别是肺癌。人类的流行病学数据显示，患有各种肺部炎性疾病（包括慢性阻塞性肺病（COPD）和哮喘等）的患者患癌症的风险增加。研究发现，炎症会促进小鼠肺肿瘤的发展。许多控制肺部炎症遗传易感性的QTL也与调节小鼠肺部肿瘤易感性的QTL共定位。布地奈德和吲哚美辛（具有抗炎活性）的给药可抑制小鼠的肺肿瘤发生，并且包括Cox 1和Cox 2在内的炎症生物标志物在小鼠和人肺癌中经常升高。炎症和肺癌之间的这些关联表明，肺部炎症似乎是肺肿瘤发生过程中的关键肿瘤促进步骤。本提案的目的是确定肺部炎症的遗传修饰剂。这些研究的意义在于，它们将确定可能也有助于人类肺癌遗传易感性的候选肺部炎症易感基因。