权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10439767
负责人：
Sonia Kupfer
金额：
$ 36.35万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439767
关键词：
ATAC-seq Affect African African American population 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 gene network 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。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metachronous Advanced Neoplasia on Surveillance Colonoscopy in Patients With Young- vs Older-onset of Colorectal Cancer.

年轻与老年结直肠癌患者监测结肠镜检查中的异时性晚期肿瘤。

DOI：
10.1016/j.cgh.2019.07.034
发表时间：
2021
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
0
作者：
Tjaden,Jamie;Muller,Charles;Wideroff,Gina;Ma,Karen;Satiya,Jinendra;Sussman,Daniel;Yen,Eugene;Kupfer,SoniaS;Melson,Joshua
通讯作者：
Melson,Joshua

Automated Analysis of Cerebrospinal Fluid Cells Using Commercially Available Blood Cell Analysis Devices-A Critical Appraisal.

DOI：
10.3390/cells10051232
发表时间：
2021-05-18
期刊：
Cells
影响因子：
6
作者：
Wick M;Gross CC;Tumani H;Wildemann B;Stangel M;On Behalf Of The German Society Of Csf Diagnostics And Clinical Neurochemistry Dgln E V
通讯作者：
On Behalf Of The German Society Of Csf Diagnostics And Clinical Neurochemistry Dgln E V

Efficacy of bevacizumab and chemotherapy in the first-line treatment of metastatic colorectal cancer: broadening KRAS-focused clinical view.

DOI：
10.1186/s12876-015-0266-6
发表时间：
2015-03-24
期刊：
BMC gastroenterology
影响因子：
2.4
作者：
Bencsikova B;Bortlicek Z;Halamkova J;Ostrizkova L;Kiss I;Melichar B;Pavlik T;Dusek L;Valik D;Vyzula R;Zdrazilova-Dubska L
通讯作者：
Zdrazilova-Dubska L

Effective Identification of Lynch Syndrome in Gastroenterology Practice.