Role of Circadian Factors in Inflammation and Colorectal Adenoma Risk

结直肠癌(CRC)是最常见和最致命的癌症之一。在南卡罗来纳州，我们的团队 已经记录了儿童权利公约的种族差距，超过了全国的比率。大多数结肠癌是由腺瘤引起的 (腺瘤性息肉)，通过筛查结肠镜检查发现。胃肠道(GI)炎症和 DNA甲基化异常是导致腺瘤形成和结直肠癌风险的关键过程。失眠和失眠 昼夜节律紊乱会引起炎症，改变DNA甲基化，增加结直肠癌的风险。非洲-- 美国人(AA)与欧洲裔美国人(EA)在内源性昼夜节律上不同，他们 与EA相比，EA更有可能睡眠不佳和压力过大(静力超负荷或“老化”)。这件案子- 对照研究将检验这一假设，即昼夜节律和睡眠的中断与 接受结肠镜检查的AA和EA患者的炎症和腺瘤风险。分子 守时由“时钟基因”控制，它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，肿瘤坏死因子α、IL-6的表达)，并且它们作为肿瘤抑制因子 (例如，‘周期’或每个基因)。我们的研究表明，PER中的基因变异或异常甲基化 基因与腺瘤风险增加有关，睡眠障碍会增加结直肠癌风险。褪黑素是 一种时钟调节的激素，通过与其结合来抑制胃肠道炎症和抑制结肠癌的生长 细胞受体(MT-1、RoRα)。这项研究将描述生物行为昼夜节律紊乱的指标 (睡眠障碍、社交时差、疲劳、压力)，以及关键的分子相关因素(PER3基因和 时钟基因[per1、per2、per3]甲基化；时钟控制基因[MT-1、RoRα、肿瘤坏死因子α、IL-6]甲基化； 全球DNA甲基化[LINE-1])，以确定它们在炎症和腺瘤风险中的作用。一种生物行为 框架将解决以下具体目标：1)在患者中进行病例对照研究 接受筛查结肠镜检查以确定昼夜节律紊乱指标(DNA甲基化， 生物行为、遗传)与腺瘤病例状态相关联，如果这种关系是 经RACE修改(N=1,000；400例，600例对照)；2)确定昼夜节律紊乱指标是否 与正常胃肠道组织炎症相关(肿瘤坏死因子α、IL-6mRNA表达)；3)确定 行为和分子昼夜节律紊乱指标相关；4)在腺瘤病例中，确定 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。我们队有一支强大的队伍 提供高质量的结肠镜检查服务以及与AA和EA社区合作的记录 研究。前瞻性数据收集(与结肠镜检查相关)和有效、定量生物行为的使用 分子措施将限制偏见的潜在引入。这项研究将严格检查 基于昼夜节律的行为和分子危险因素与胃肠道炎症和结直肠的关系 腺瘤风险。基于昼夜节律的危险因素可作为预防结直肠癌的新的、可修改的靶点。

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.