Role of Alcohol and Circadian Disruption in Inflammation and Colon Cancer

酒精和昼夜节律紊乱在炎症和结肠癌中的作用

• 批准号: 8798555
• 负责人: ALI KESHAVARZIAN
• 金额: $ 34.08万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-05 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8798555
• 关键词: Address; Alcohol consumption; Alcohols; Attention; Automobile Driving; Benign; Biological; Bone Marrow; Bone Marrow Cells; CD4 Positive T Lymphocytes; Carcinogens; Cell Communication; Cell physiology; Cells; Chimerism; Chronic; Circadian Rhythms; Colon; Colon Carcinoma; Colorectal Cancer; Dendritic Cells; Development; Distal; Dominant-Negative Mutation; Eating; Environment; Environmental Risk Factor; Epidemiologic Studies; Ethanol; Food; Functional disorder; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Goals; Health; Health Hazards; Homeostasis; Hour; Human; Immune; Immunologics; Individual; Inflammation; Inflammatory Bowel Diseases; Instruction; Intervention; Intestines; Knowledge; Large Intestine; Lead; Life; Life Style; Light; Link; Malignant Neoplasms; Mediating; Mitotic; Modeling; Molecular; Mucosal Immunity; Mucositis; Mus; Outcome; Pathologic; Pattern; Peripheral; Physiological; Play; Polyps; Predisposing Factor; Predisposition; Prevention; Prevention therapy; Principal Investigator; Process; Regulation; Regulatory T-Lymphocyte; Risk; Role; Schedule; Sentinel; Series; Sleep Wake Cycle; Small Intestines; Societies; Testing; Work; alcohol consequences; base; cancer prevention; cancer risk; carcinogenesis; cell type; circadian pacemaker; feeding; food restriction; genetic approach; ileum; immunopathology; mast cell; mouse model; mutant; novel; polyposis; problem drinker; research study; shift work; targeted treatment; treatment strategy

Alcohol intake contributes to serious health issues including colorectal cancer (CRC). However, the exact mechanism(s) of ethanol-associated carcinogenesis, have remained obscure, as ethanol itself is not a carcinogen. Circadian disruption is a common feature among alcoholics. Epidemiological studies have linked non-traditional work schedules (e.g., shift work) with increased risks of cancer. The overall goal of this Project is to establish that alcohol consumption contributes to serious risk of colon cancer when combined with desynchronization of circadian rhythms and to reveal the underiying cellular immunologic mechanisms. We have evidence for inflammation driving polyposis, for mast cells orchestrating inflammation, and for regulation of mast cells and inflammation by Tregs. Alcohol fed mice whose circadian rhythms were disrupted by chronic shifting of the light/dark cycle developed overt intestinal and colonic inflammation, resulting in expanded mitotic proliferation zone and crypt elongation. We hypothesize that alcohol and desynchronization of circadian rhythms act synergistically to increase inflammation and susceptibility to colon cancer. Here we propose to test this hypothesis in a novel mouse model: mice that spontaneously develop benign polyps in their colon and distal ileum. In Aim 1 we will establish the extent to which alcohol synergizes with environmental desynchronization of central and peripheral circadian rhythms through light/dark shift and food restriction to cause inflammation, exacerbate polyposis, and promote CRC. The role of mast cells and Tregs in this process will be addressed by genetic and pharmacologic interventions. In Aim 2, we will use a genetic approach to establish that the circadian disruption of immune cells plays a considerable role in pathophysiology of alcohol induced colon cancer. We will generate through bone marrow chimerism mice that are predisposed to polyposis and also express a dominant negative Clock mutant in the immune compartment. The proposed studies are significantly relevant as a potential model for humans engaged in lifestyle-related disruption of proper circadian organization.Our findings will provde new paradigms for cancer prevention and targeted therapy. RELEVANCE (See instructions): Alcohol promotes cancer develoment/progression in a subset of individuals; however, it is not clear what factor(s) confer susceptibility. Identification of disrupted circadian rhythms as a predisposing factor for cancer devebpment/progression may.lead to new prevention strateges or treatment strategies (i.e., chronobiological therapy and/or pro- or pre-biotics) for alcohol-induced cancer.

酒精摄入会导致严重的健康问题，包括大肠癌（CRC）。但是，确切的 乙醇相关的癌变的机制一直晦涩难懂，因为乙醇本身不是 致癌物。昼夜节律破坏是酗酒者的共同特征。流行病学研究已关联 非传统工作时间表（例如，轮班工作），癌症风险增加。总体目标 项目是确定饮酒会导致结肠癌的严重风险 通过昼夜节律的异步化，并揭示了细胞免疫学机制不足。 我们有证据表明炎症驱动息肉病，肥大细胞修复炎症以及用于 调节肥大细胞和Treg炎症。酒精喂养的昼夜节律是 由于光/黑暗周期的慢性变化而破坏了明显的肠道和结肠炎症， 导致有丝分裂增殖区和隐窝伸长延伸。我们假设酒精和 昼夜节律行为的不同步协同炎症和易感性 结肠癌。在这里，我们建议在新的小鼠模型中检验这一假设：自发的小鼠 在其结肠和远端回肠中发展良性息肉。在目标1中，我们将确定酒精的程度 与环境之间的环境解调协同，通过 轻/深度转移和食物限制会引起炎症，加剧息肉病并促进CRC。角色 在此过程中，肥大细胞和Treg将通过遗传和药理干预措施来解决。目标 2，我们将使用一种遗传方法来确定免疫细胞的昼夜节律破坏作用 酒精诱导结肠癌的病理生理学作用很大。我们将通过骨头产生 骨髓嵌合小鼠易于息肉病，也表达了主导的负钟 免疫区室中的突变体。拟议的研究与作为潜在模型显着相关 人类从事与生活方式相关的昼夜节律组织的破坏。我们的发现将为新 预防癌症和靶向治疗的范例。 相关性（请参阅说明）： 酒精促进了一个个体的一部分癌症的癌症/进展；但是，尚不清楚什么 因子赋予敏感性。鉴定破坏的昼夜节律是诱发因素 癌症疾病/进展可能会导致新的预防策略或治疗策略（即 用于酒精诱导的癌症的时间生物学疗法和/或培养基或培养基。