Identification of Pulmonary Lung Tumor Resistance 1 QTL Candidates

肺肿瘤抗性1 QTL候选者的鉴定

• 批准号: 7474739
• 负责人: MING YOU
• 金额: $ 33.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-16 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474739
• 关键词: A/J Mouse; Accounting; Alleles; Apoptosis; Backcrossings; Biological Assay; Candidate Disease Gene; Cell Cycle; Cell Line; Cell Proliferation; Cells; Characteristics; Chromosomes, Human, Pair 11; Code; Complementary DNA; Congenic Strain; DNA Sequence; Databases; Development; Environmental Carcinogens; Exhibits; Genes; Genetic; Genetic Heterogeneity; Genetic Polymorphism; Genetic Predisposition to Disease; Genomics; Goals; Growth; Human; In Vitro; Inbred Mouse; Inbred Strains Mice; Knock-in Mouse; Lod Score; Lung; Lung Adenoma; Lung Neoplasms; Malignant neoplasm of lung; Maps; Mitotic Cell Cycle; Mouse Strains; Mus; Names; Nude Mice; Phenotype; Predisposition; Production; Quantitative Trait Loci; Resistance; Role; Series; Smoke; Susceptibility Gene; Tumor Suppressor Proteins; Variant; adenoma; base; chemical carcinogen; congenic; environmental agent; gene environment interaction; genetic linkage; genetic linkage analysis; genome database; genome sequencing; lung basal segment; lung carcinogenesis; lung tumorigenesis; mouse model; neoplastic cell; positional cloning; size; tumor; tumorigenic

DESCRIPTION (provided by applicant): This application will focus on genetic susceptibility to lung adenoma induction to environmental carcinogens. Linkage analysis previously mapped a lung adenoma resistance quantitative trait locus (QTL) named pulmonary adenoma resistance 1 locus or Par1 which is located on mouse chromosome 11. The Par1 locus confers protection against lung adenoma development. Contributed by M. spretus allele, Par1 locus accounts for 23% of lung adenoma resistance phenotype to chemical carcinogens when co-expressed with highly penetrant Pas1 allele of the A/J strain. The goal of this proposal is to identify the Par1 gene, which is responsible for lung adenoma resistance to chemical carcinogens. The Par1 QTL mapping result has been confirmed by the production of congenic strains in which adenoma resistant M. spretus allele was substituted onto the genetic background of the A/J mouse. Next, the Par1 locus 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 0.2-0.5 cM, which is expected to be small enough for positional cloning. 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 M. spretus mice. Effect of the candidate Par1 genes on tumorigenic and growth characteristics of mouse lung cells will be examined in vitro. The functional role of the candidate Par1 gene in mouse lung carcinogenesis will be evaluated by constructing knock-in mice. The resulting knock-in mice will be subjected to lung carcinogenesis assay to confirm the Par1 gene. The significance of these studies is that they will identify the Par1 gene and facilitate our understanding of genetic basis of lung adenoma induction by environmental carcinogens.

描述（由申请人提供）：本申请将集中于对环境致癌物诱导肺腺瘤的遗传敏感性。链接分析先前绘制了一个肺腺瘤抗性定量性状基因座（QTL），称为肺腺瘤抗性1基因座或PAR1，位于小鼠染色体11上。PAR1基因座赋予肺腺瘤发育的保护。 PAR1基因座由M. spretus等位基因贡献，占化学致癌物的肺腺瘤耐药表型的23％，当时与A/J菌株的高渗透率PAS1等位基因共表达时。该提案的目的是识别PAR1基因，该基因负责肺腺瘤对化学致癌物的耐药性。 PAR1 QTL映射结果已通过产生先天性菌株的产生，其中将抗腺瘤的SPRETUS等位基因取代在A/J小鼠的遗传背景上。接下来，通过生产亚综合小鼠应变逐渐减少QTL区域，将其缩小到0.2-0.5 cm左右，预计将其缩小到大约0.2-0.5 cm左右，预计将其缩小到大约0.2-0.5 cm，以缩小QTL区域，预计将其缩小到大约0.2-0.5 cm。整个狭窄区域的DNA序列将通过完成的小鼠基因组数据库获得。将根据已知或推导的功能和/或SPRETUS小鼠的表达差异来鉴定目标区域中的新基因和候选基因。将在体外检查候选PAR1基因对小鼠肺细胞的致瘤和生长特征的影响。候选PAR1基因在小鼠肺癌发生中的功能作用将通过构造敲入小鼠进行评估。由此产生的敲入小鼠将进行肺癌发生测定，以确认PAR1基因。这些研究的意义在于它们将鉴定PAR1基因，并促进我们对环境致癌物诱导肺腺瘤诱导的遗传基础的理解。