Functional Studies of Candidate Lung Cancer Susceptibility Genes

候选肺癌易感基因的功能研究

• 批准号: 8550775
• 负责人: Christopher I. Amos
• 金额: $ 52.34万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550775
• 关键词: 15q; 15q24; Affect; African American; Animal Model; Apoptosis; Area; Biological; Biological Assay; Cancer-Predisposing Gene; Candidate Disease Gene; Caucasians; Caucasoid Race; Cell Culture Techniques; Cell Proliferation; Chromosomes; DNA Methylation; Development; Epigenetic Process; Evaluation; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetically Engineered Mouse; Goals; Human; In Vitro; Inherited; Lead; Malignant Neoplasms; Malignant neoplasm of lung; Methylation; Neurons; Nicotine; Nicotinic Receptors; Phenotype; Population; Predisposition; Property; Research; Risk; Risk Behaviors; Role; Smoking Behavior; Susceptibility Gene; Testing; Tobacco smoke; Variant; base; cancer cell; cancer risk; gene environment interaction; genome wide association study; in vivo; mouse model; receptor

PROJECT SUMMARY (See instmctions): As a result of the already complete GWAS studies, outstanding loci for further functional characterization have already been identified. In particular, and as described in more detail below, the rs1696698 SNP in the nicotinic acetycholine receptor unit 5 (CHRNAS) influences risk for lung cancer and affects smoking behavior and has also been shown to affect the activity of the multimeric nicotinic receptor in vitro. While this variant has important effects on nicotine receptor activity, extensive studies in Caucasian and African-American populations show that it is not the only variant influencing lung cancer risk and smoking behavior in the region of chromosomes 15q24-25.1, and the effects of rsl 696698 remain poorly characterized. Therefore, we plan further studies to define effects of variations in this region on nicotinic receptor activity, expression of the genes in the region and on effects of variations on cellular phenotypes relating to cancer development and progression. In addition, GWAS studies have identified excellent candidates on chromosomes 5p and 6p that wanrant further detailed analyses. For aim 1 of area 2 we propose to characterize methylation for the loci that have been identified. We also propose additional cellular phenotype based assays for loci that have been identified and the evaluation of phenotypes in existing animal models. Aim 2 of area 2 will detemiine the effect of CHRNA3/CHRNA5 polymorphisms on the biophysical and pharmacological properties of neuronal nicotinic acetylcholine receptors (nAChRs). We also propose additional cellular phenotype based assays for loci that have been identified and the evaluation of phenotypes in existing and new animal models (Aims 3 & 4 of area 2)..

项目摘要（请参阅Instmctions）： 由于已经完整的GWAS研究，已经确定了用于进一步功能表征的出色基因座。尤其是，如下所述，烟碱乙酸乙酸盐受体单元5（CHRNA）中的RS1696698 SNP影响了肺癌的风险并影响吸烟行为，并且还显示出影响多聚体烟碱受体在体外的活性。尽管这种变体对尼古丁受体的活性具有重要影响，但对白种人和非裔美国人种群的广泛研究表明，它并不是影响肺癌风险和吸烟行为15q24-25.1区域的唯一变体，RSL 696698的影响仍然较差。因此，我们计划进一步的研究，以确定该区域的变化对烟碱受体活性的影响，该区域中基因的表达以及对与癌症发展有关的细胞表型变异的影响 和进展。此外，GWAS研究已经确定了染色体5p和6p的出色候选者，这些候选者进一步详细介绍了分析。对于区域2的AIM 1，我们建议表征已鉴定的基因座的甲基化。我们还提出了已鉴定出的基因座基于基因型的其他细胞表型测定，并在现有动物模型中评估了表型。区域2的AIM 2将对CHRNA3/CHRNA5多态性的影响对神经元烟碱乙酰胆碱受体（NACHRS）的生物物理和药理特性的影响。我们还提出了已鉴定出的基因座的其他基于细胞表型的测定，并在现有动物模型和新动物模型中评估表型（AIM 2和2区域2）。