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

非洲裔和欧洲裔美国人的结肠对维生素 D 和阿司匹林的反应

• 批准号: 10196994
• 负责人: Sonia Kupfer
• 金额: $ 37.12万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-03 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196994
• 关键词: ATAC-seq; Affect; African; African American; Alleles; American; Apoptosis; Aspirin; Attention; Binding; Biological; Biological Assay; Biology; Candidate Disease Gene; Cellular Assay; Chemoprevention; Chemopreventive Agent; Chromatin; Clinical; Clinical Treatment; Colon; Colon Carcinoma; Colorectal Cancer; Data; Development; Disease; Environmental Risk Factor; Epigenetic Process; Ethnic Origin; European; Exhibits; Experimental Models; Funding; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomic Segment; Genomics; Human; Individual; Integration Host Factors; Laboratories; Learning; Luciferases; Malignant Neoplasms; Maps; Measures; Modeling; Organoids; Outcome; Pathway interactions; Phenotype; Play; Population; Prevention strategy; Publishing; Reporter; Role; Sample Size; Single Nucleotide Polymorphism; Systems Biology; Testing; Tissues; United States National Institutes of Health; Vitamin D; Work; base; cancer health disparity; cancer risk; cohort; colorectal cancer prevention; colorectal cancer risk; differential expression; epigenomics; ethnic difference; genetic architecture; genome wide association study; genome-wide; health disparity; high risk; innovation; novel marker; prevent; preventive intervention; response; risk stratification; stem cells; success; targeted agent; transcription factor; transcriptome sequencing; treatment effect; treatment response

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.

项目摘要/摘要 在美国，非裔美国人（AA）的结直肠癌（CRC）最大，生物学 这种差异的原因尚不完全理解。主机与环境之间的互动 已知包括化学预防治疗在内的因素可以改变CRC风险，并且有新的证据 AA和欧洲美国人（EA）的治疗效应差异对于这两个最有前途的 化学预防剂，维生素D和阿司匹林。我们广泛的目标是建模和了解如何相互 治疗反应的种族差异可能导致CRC差异。我们的实验室已经优化了 干细胞衍生的人类器官培养物研究个体之间的细胞反应 使用传统型号可行。在此提案中，我们使用结肠机身来检验中心假设 AA和/或阿司匹林对维生素D和/或阿司匹林的转录，染色质的可及性和细胞反应不同 EA，这些种族间差异可能会影响CRC风险和临床治疗反应。 我们以前用活性维生素D（1,25D）和 确定了几种具有种族间反应差异的基因。与种族间寻找基因的成功 响应差异为将我们全基因组方法扩展到1,25D，阿司匹林和 在更大样本的结肠器官（80 aa＆80 ea）中的组合处理以实现更大的功率 确定转录网络和染色质可及性的种族间差异。我们将 在独立的器官队列中重复观察到的差异以及与癌症相关的细胞的测试 处理的类器官（50 AA＆50 EA）的子集中的处理表型（AIM 1）。此外，使用RNA-seq数据 在AIM 1中获得，我们将测试对个人之间的反应差异的遗传贡献 种族使用特定于等位基因的表达。鉴定的响应基因和SNP将进行测试 来自NIH资助的CRC GWA和化学预防试验的基因和SNP之间的富集以及 使用功能测定法进行机械测试（AIM 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 结肠中对维生素D和阿司匹林的反应以及它们如何通过种族差异，ii）连接细胞反应 具有CRC风险和对化学预防的反应，iii）将基因和SNP识别为机械研究的基因和SNP 以及可能发展为个性化CRC预防的新型生物标志物，以最终， 减少CRC差异。