Colonic responses to vitamin D and aspirin in African- and European-Americans

项目摘要/摘要 在美国，非裔美国人(AA)患结直肠癌(CRC)的负担最大，生物学上 造成这种差异的原因仍然不完全清楚。寄主与环境的相互作用 众所周知，包括化学预防治疗在内的因素可以改变结直肠癌的风险，而且有新的证据表明。 AA和欧洲美国人(EA)对这两种最有希望的患者的治疗效果的差异 化学预防药物、维生素D和阿司匹林。我们的广泛目标是建立模型并了解 治疗反应中的种族差异可能会导致儿童权利公约的差异。我们的实验室已经优化了 干细胞来源的人类器官培养，以研究尚未被 使用传统模型是可行的。在这项提议中，我们使用结肠有机化合物来检验中心假设 再生障碍性贫血和/或阿司匹林的转录、染色质可及性和细胞对维生素D和/或阿司匹林的反应不同 这些种族间的差异可能会影响CRC的风险和临床治疗反应。 我们之前用活性维生素D(1，25D)和 确定了几个具有种族间反应差异的基因。成功地发现了跨种族的基因 反应差异为将我们的全基因组方法扩展到1，25D，阿司匹林和 在更大样本量的结肠有机化合物(80AA和80EA)中进行联合治疗，以实现更大的功率 以确定在转录网络以及染色质可获得性方面的种族差异。我们会 在一组独立的有机化合物中复制观察到的差异，并测试与癌症相关的细胞 处理过的有机物(50个氨基酸和50个EA)子集的处理表型(目标1)。此外，使用RNA-seq数据 在目标1中获得的，我们将测试个体和 使用等位基因特异性表达的种族。已确定的反应基因和SNPs将被检测 美国国立卫生研究院资助的CRGWA和化学预防试验中的基因和SNP的浓缩以及 使用功能分析进行机械测试(目标2)。 我们创新研究的结果将：i)阐明潜在的生物学和遗传结构 结肠对维生素D和阿司匹林的反应以及它们在种族上的差异，ii)连接细胞反应 与结直肠癌风险和对化学预防的反应，以及iii)识别用于机制研究的基因和SNPs 以及作为个性化CRC预防的新生物标志物的可能开发，以便最终， 减少儿童权利公约的差距。

PROJECT SUMMARY/ABSTRACT African Americans (AA) have the greatest burden of colorectal cancer (CRC) in the US, and biological reasons for this disparity remain incompletely understood. Interactions between host and environmental factors, including chemopreventive treatments, are known to modify CRC risk, and there is emerging evidence of differences in treatment effects between AA and European Americans (EA) for the two most promising chemopreventive agents, vitamin D and aspirin. Our broad objective is to model and understand how inter- ethnic differences in treatment responses could contribute to CRC disparities. Our laboratory has optimized stem cell-derived human organoid cultures to study cellular responses between individuals that have not been feasible using traditional models. In this proposal, we use colonic organoids to test the central hypothesis that transcriptional, chromatin accessibility and cellular responses to vitamin D and/or aspirin differ between AA and EA, and that these inter-ethnic differences could impact CRC risk and clinical treatment response. We previously treated ex vivo primary colon tissue from AA and EA with active vitamin D (1,25D) and identified several genes with inter-ethnic response differences. The success of finding genes with inter-ethnic response differences provides rationale for extending our genome-wide approach to 1,25D, aspirin and combination treatments in a larger sample size of colonic organoids (80 AA & 80 EA) to achieve greater power to identify inter-ethnic differences in transcriptional networks as well as chromatin accessibility. We will replicate observed differences in an independent cohort of organoids as well as test for cancer-relevant cellular treatment phenotypes in a subset of treated organoids (50 AA & 50 EA) (Aim 1). Further, using RNA-seq data obtained in Aim 1, we will test for a genetic contribution to response differences between individuals and ethnicities using allele specific expression. The response genes and SNPs identified will be tested for enrichment among genes and SNPs from NIH-funded CRC GWAS and chemoprevention trials as well as tested mechanistically using functional assays (Aim 2). The outcomes of our innovative study will: i) elucidate underlying biology and genetic architecture of responses to vitamin D and aspirin in the colon and how they differ by ethnicity, ii) connect cellular response with CRC risk and response to chemoprevention, and iii) identify genes and SNPs for mechanistic studies as well as for possible development as novel biomarkers for personalized CRC prevention in order to, ultimately, reduce CRC disparities.