DNA repair, Cell cycle Checkpoints and Apoptosis and Bladder Cancer Risk

我的长期目标是成为一名独立的分子流行病学家，在遗传学和 先进的统计方法，以便能够分析高通量基因变异数据， 癌症易感性中的基因和基因-环境相互作用。我的职业发展计划包括： 课程/研讨会，与人类遗传学、癌症生物学和高级生物学领域的导师举行会议 统计方法我的研究计划将集中在膀胱癌（BC）的遗传易感性。我建议 从一项正在进行的病例对照研究中利用流行病学和遗传标记数据的可用性， “膀胱癌遗传易感性的标志物”（R 01 CA 74880，PI：Xifeng. Wu）.目前的研究 包括超过2,500例BC病例和对照组，其中大多数是白人，在性别、年龄和种族上相匹配。我的目标是 使用最先进基因分型技术鉴定赋予膀胱癌易感性的新基因座， 统计学和生物信息学工具。具体目标是：1）提高我在遗传学方面的知识和技能 和统计学，以确定新的遗传位点作为易感性标记的BC通过扩展原始45潜力 功能性SNP包括DNA修复、细胞周期控制和细胞周期调控基因中的另外2112个标签SNP。 使用Illumina Golden Gate Assay在800例高加索人和800例高加索人对照中的凋亡途径; 2） 评估单倍型和双倍型作为易感性标记; 3）使用生物信息学工具评估 SNPs在DNA修复、细胞周期控制和凋亡途径中的功能意义， DNA修复和细胞周期控制的基因型数据与来自表型测定的功能数据。的 第二个目标是应用分层模型来完善风险评估，并应用新的机器学习 探索任何影响BC风险的基因-环境和基因-基因相互作用的工具。 我的项目补充了父母的资助，因为它：1）将标记SNP添加到潜在的功能SNP中 2）增加了单倍型分析; 3）提出了新的统计和生物信息学方法。 相关性（参见说明）： 膀胱癌是一种与烟草有关的癌症，是美国男性中第四大常见癌症。 只有一小部分吸烟者会患膀胱癌，这表明他们对这种疾病有遗传易感性。这 研究将鉴定新遗传标记物，这些标记物可用作鉴定高危人群的生物标记物， 可以成为干预计划的目标。

My long-term goal is to become an independent molecular epidemiologist with in-depth training in genetics and advanced statistical methods in order to be able to analyzehigh throughput gene variant data to explore gene- gene and gene-environment interactions in cancer susceptibility. Mycareer development plan includedidatic courses/seminars, meetings with mentors in the areas of human genetics, cancer biology and advanced statistical methods. Myresearch proposal will focus on genetic susceptibility of blader cancer (BC). I propose to capitalize on availabilityof epidemiologicand genentic marker data from an on-going case-control study, "Markers of GeneticSusceptibilityto Bladder Cancer"(R01 CA74880,PI:Xifeng. Wu). The parent study currently include over 2,500,mostly Caucasian,BCcases and controls, matched on sex, age and ethnicity. Mygoal is to identify novel loci that confer bladder cancer susceptibility using state-of-the-art genotyping techology and novel statistical and bioinformaticstools. The Specific Aims are: 1) To enhance my knowledge and skills in genetics and statistics to identify novel genetic loci as susceptibility markers of BC by extending the original45 potential functional SNPs to include additional 2112 tagging SNPs in genes in the DNArepair, cell cycle control and apoptotic pathways in 800 Caucasiancases and 800 Caucasiancontrols using the Illumina Golden Gate Assay; 2) To assess haplotypes and diplotypes as markers of susceptibility; 3) To use bioinformaticstools to assess functional significance of SNPs in the DNArepair, cell cycle control and apoptotic pathways and to correlate genotype data of DNArepair and cell cycle control with functional data derived from phenotypic assays. The secondary aim is to apply hierarchical models to refine risk assessment and to apply novel machine-learning tools to explore any gene-environment and gene-gene interactions influencing BCrisk. My project complements the parent grant in that it: 1) adds tagging SNPs to potential functional SNPs addressed in the parent grant; 2) adds haplotype analyses; 3) proposes novel statistical and bioinformaticsapproaches. RELEVANCE (See instructions): Bladder cancer is a tobacco-related cancer which is the fourth most common cancer in men in U.S. The fact that only a fraction of smokers develop bladder caricer indicating genetic susceptibility to the disease. This study will identify novel genetic markers may be useful as biomarkers to identify high-risk populationsthat could then be targeted for intervention programs.