Role of Circadian Factors in Inflammation and Colorectal Adenoma Risk

昼夜节律因素在炎症和结直肠腺瘤风险中的作用

基本信息

批准号：
10470006
负责人：
James Burch
金额：
$ 59.8万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-11 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10470006
关键词：
Aberrant DNA Methylation Address Adenomatous Polyps Adverse effects African African American population American Anti-Inflammatory Agents Apoptosis Automobile Driving Behavioral Binding Biological Factors Case-Control Studies Cell Proliferation Cell physiology Chronic Circadian Dysregulation Circadian Rhythms Circadian gene expression Colonic Neoplasms Colonoscopy Colorectal Adenoma Colorectal Cancer Communities DNA Methylation DNA Repair Data Collection Detection Development Diet Early Diagnosis Endocrine Epigenetic Process European Fatigue Gastrointestinal tract structure Gene Expression Genes Genetic Genetic Variation Genotype Hormone secretion Hormones Human Immune Immunologic Surveillance Immunosuppression Incidence Inflammation Inflammation Mediators Inflammatory Interleukin-6 Jet Lag Syndrome Leukocytes Light Link Malignant Neoplasms Measures Mediating Melatonin Methylation Minisatellite Repeats Molecular Normal tissue morphology Oncogenes PTGS2 gene Pathway interactions Patients Pattern Peripheral Play Predisposition Prevention Prevention trial Process Race Research Retrospective cohort study Risk Risk Factors Role Seminal Services Signal Transduction Sleep Sleep Deprivation Sleep Disorders Sleep disturbances South Carolina Stress Study Section Symptoms TNF gene Testing Tissues Tumor Suppressor Proteins United States Variant Weather XPA gene adenoma base beta catenin biobehavior c-myc Genes cancer health disparity cancer risk case control circadian colorectal cancer prevention colorectal cancer risk cyclooxygenase 2 design diet and exercise experience gastrointestinal human tissue improved inhibitor mRNA Expression malignant breast neoplasm modifiable risk mortality novel physical inactivity poor sleep promoter prospective racial difference receptor screening screening disparities shift work social socioeconomics transcriptome tumor tumor growth

项目摘要

Colorectal cancer (CRC) is among the most common and deadly forms of cancer. In South Carolina, our group has documented racial CRC disparities that exceed national rates. Most colon tumors arise from adenomas (adenomatous polyps) that are detected via a screening colonoscopy. Gastrointestinal (GI) inflammation and aberrant DNA methylation are key processes driving adenoma formation and CRC risk. Sleep loss and circadian rhythm disruption can induce inflammation, alter DNA methylation, and increase CRC risk. African- Americans (AAs) differ from European-Americans (EAs) in their endogenous circadian timing, and they are more likely than EAs to have poor sleep and excessive stress (allostatic overload or ‘weathering’). This case- control study will test the hypothesis that disruption of circadian processes and sleep is associated with inflammation and adenoma risk among AA and EA patients receiving a screening colonoscopy. Molecular timekeeping is controlled by ‘clock genes’ that regulate circadian gene expression via epigenetic mechanisms. Clock genes can modulate inflammation (e.g., TNFα, IL-6 expression), and they act as tumor suppressors (e.g., the ‘Period’ or PER genes). Our research suggests that genetic variation or aberrant methylation in PER genes is associated with increased adenoma risk, and that sleep disorders can increase CRC risk. Melatonin is a clock-regulated hormone that suppresses GI inflammation and inhibits colon tumor growth by binding to its cellular receptors (MT-1, RORα). This study will characterize biobehavioral circadian disruption indicators (sleep disturbances, social jet lag, fatigue, stress), along with key molecular correlates (PER3 genotype and methylation of: clock genes [PER1, PER2, PER3]; clock-controlled genes [MT-1, RORα, TNFα, IL-6]; and global DNA methylation [LINE-1]) to determine their role in inflammation and adenoma risk. A biobehavioral framework will address the following Specific Aims: 1) Conduct a case-control study among patients undergoing a screening colonoscopy to determine whether circadian disruption indicators (DNA methylation, biobehavioral, genetic) are associated with adenoma case status relative to controls, and if the relationship is modified by race (N=1,000; 400 cases, 600 controls); 2) Determine if circadian disruption indicators are associated with inflammation in normal GI tissue (TNFα, IL-6 mRNA expression); 3) Determine whether behavioral and molecular circadian disruption indicators are related; 4) Among adenoma cases, determine if methylation of candidate circadian genes in adenomas differs from normal GI tissue. Our team has a strong track record of providing high quality colonoscopy services and in engaging AA and EA communities in research. Prospective data collection (relative to colonoscopy) and the use of valid, quantitative biobehavioral and molecular measures will limit the potential introduction of bias. This study will rigorously examine circadian-based behavioral and molecular risk factors as they relate to GI inflammation and colorectal adenoma risk. Circadian-based risk factors may serve as novel, modifiable targets for CRC prevention.

在南卡罗来纳州，结直肠癌 (CRC) 是最常见和最致命的癌症之一。有记录显示，结直肠癌的种族差异超过了全国范围内的比率。大多数结肠肿瘤源自腺瘤。（腺瘤性息肉）通过筛查结肠镜检查发现的胃肠道（GI）炎症和异常 DNA 甲基化是导致腺瘤形成和 CRC 风险的关键过程。昼夜节律紊乱会诱发炎症、改变 DNA 甲基化并增加非洲结直肠癌的风险。美国人 (AA) 与欧洲美国人 (EA) 的内源昼夜节律不同，而且他们比 EA 更有可能睡眠不佳和压力过大（动态负荷过重或“风化”）。对照研究将检验昼夜节律过程和睡眠的破坏与以下因素相关的假设：接受分子结肠镜检查的 AA 和 EA 患者的炎症和腺瘤风险。计时是由“时钟基因”控制的，“时钟基因”通过表观遗传机制调节昼夜节律基因的表达。时钟基因可以调节炎症（例如 TNFα、IL-6 表达），并且它们可以充当肿瘤抑制因子（例如，“Period”或 PER 基因）。我们的研究表明 PER 中存在遗传变异或异常甲基化。基因与腺瘤风险增加有关，而睡眠障碍会增加结直肠癌风险。一种时钟调节激素，通过与其结合来抑制胃肠道炎症并抑制结肠肿瘤生长细胞受体（MT-1、RORα）。这项研究将表征生物行为昼夜节律紊乱指标。（睡眠障碍、社交时差、疲劳、压力），以及关键分子相关因素（PER3 基因型和时钟基因 [PER1、PER2、PER3] 的甲基化；以及整体 DNA 甲基化 [LINE-1]）以确定其在炎症和腺瘤风险中的作用。该框架将实现以下具体目标： 1) 在患者中进行病例对照研究接受结肠镜筛查以确定是否存在昼夜节律紊乱指标（DNA 甲基化、生物行为、遗传）与相对于对照的腺瘤病例状态相关，如果这种关系是按种族修改（N=1,000；400 个病例，600 个对照）；2) 确定昼夜节律紊乱指标是否存在与正常胃肠道组织中的炎症相关（TNFα、IL-6 mRNA表达）；行为和分子昼夜节律紊乱指标是相关的；4) 在腺瘤病例中，确定是否腺瘤中候选昼夜节律基因的甲基化与正常胃肠道组织不同，我们的团队有很强的研究能力。提供高质量结肠镜检查服务以及让 AA 和 EA 社区参与其中的记录研究。前瞻性数据收集（相对于结肠镜检查）和有效的定量生物行为的使用。分子措施将限制潜在的偏见。本研究将严格检查。基于昼夜节律的行为和分子风险因素，因为它们与胃肠道炎症和结直肠相关基于昼夜节律的风险因素可以作为结直肠癌预防的新的、可改变的目标。