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，包括结直肠癌 (CRC)。然而，确切的 与乙醇相关的致癌机制仍不清楚，因为乙醇本身并不是一种 致癌物质。昼夜节律紊乱是酗酒者的一个共同特征。流行病学研究已将 非传统工作安排（例如轮班工作）会增加患癌症的风险。本次活动的总体目标 该项目旨在确定饮酒与饮酒相结合会导致严重的结肠癌风险 昼夜节律不同步并揭示潜在的细胞免疫机制。 我们有证据表明炎症驱动息肉病、肥大细胞协调炎症以及 Tregs 调节肥大细胞和炎症。酒精喂养小鼠的昼夜节律 因光/暗循环的慢性转变而受到干扰，导致明显的肠道和结肠炎症， 导致有丝分裂增殖区扩大和隐窝伸长。我们假设酒精和 昼夜节律的不同步协同作用会增加炎症和易感性 结肠癌。在这里，我们建议在一种新的小鼠模型中测试这一假设：自发地 在结肠和回肠远端形成良性息肉。在目标 1 中，我们将确定酒精的程度 通过与中枢和外周昼夜节律的环境去同步化产生协同作用 明暗转换和食物限制会引起炎症、加剧息肉病并促进结直肠癌。角色 肥大细胞和调节性T细胞在此过程中的作用将通过遗传和药理学干预来解决。瞄准 2，我们将使用遗传方法来确定免疫细胞的昼夜节律破坏发挥着作用 在酒精诱发的结肠癌的病理生理学中发挥着重要作用。我们将通过骨骼生成 骨髓嵌合小鼠易患息肉病并表达显性阴性时钟 mutant in the immune compartment.拟议的研究作为潜在模型具有重要意义 人类会因生活方式而扰乱正常的昼夜节律组织。我们的研究结果将提供新的见解 癌症预防和靶向治疗的范例。 相关性（参见说明）： 酒精会促进一部分人的癌症发生/进展；然而，尚不清楚是什么 因素赋予易感性。识别昼夜节律紊乱作为诱发因素 癌症的发展/进展可能会导致新的预防策略或治疗策略（即， 时间生物学疗法和/或益生元或益生元）用于酒精诱发的癌症。