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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要在美国，非裔美国人 (AA) 的结直肠癌 (CRC) 负担最大，而生物因素造成这种差异的原因尚不完全清楚。宿主与环境之间的相互作用已知包括化学预防治疗在内的因素会改变结直肠癌风险，并且有新的证据 AA 和欧洲裔美国人 (EA) 对于两种最有希望的治疗效果的差异化学预防剂、维生素 D 和阿司匹林。我们的总体目标是建模并理解如何交互治疗反应中的种族差异可能会导致结直肠癌的差异。我们实验室优化了干细胞衍生的人类类器官培养物，用于研究未经干细胞培养的个体之间的细胞反应使用传统模型可行。在这个提案中，我们使用结肠类器官来检验中心假设： AA 和阿司匹林的转录、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 EA 认为，这些种族间差异可能会影响 CRC 风险和临床治疗反应。我们之前用活性维生素 D (1,25D) 处理来自 AA 和 EA 的离体原代结肠组织，确定了几个具有种族间反应差异的基因。跨种族基因寻找的成功反应差异为将我们的全基因组方法扩展到 1,25D、阿司匹林和对更大样本量的结肠类器官（80 AA 和 80 EA）进行联合治疗以获得更大功效识别转录网络以及染色质可及性的种族间差异。我们将复制独立类器官队列中观察到的差异以及癌症相关细胞的测试经处理的类器官子集（50 AA 和 50 EA）的治疗表型（目标 1）。此外，使用 RNA-seq 数据在目标 1 中获得的结果，我们将测试遗传对个体和个体之间反应差异的贡献。使用等位基因特异性表达的种族。将测试确定的反应基因和 SNP 来自 NIH 资助的 CRC GWAS 和化学预防试验以及化学预防试验的基因和 SNP 的富集使用功能测定进行机械测试（目标 2）。我们的创新研究的结果将：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因种族而异的差异，ii) 连接细胞反应 CRC 风险和对化学预防的反应，以及 iii) 确定用于机制研究的基因和 SNP：以及可能开发为个性化 CRC 预防的新型生物标志物，以便最终，减少 CRC 差异。