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: 9000093
• 负责人: ALI KESHAVARZIAN
• 金额: $ 46.01万
• 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/9000093
• 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; Helper-Inducer T-Lymphocyte; 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; Probiotics; 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; prebiotics; 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）。但具体 乙醇相关致癌作用的机制仍然不清楚，因为乙醇本身并不是一种致癌物质。 致癌物质昼夜节律紊乱是酗酒者的一个共同特征。流行病学研究表明 非传统的工作时间表（例如，轮班工作）与癌症的风险增加。总的目标是 该项目旨在确定酒精消费与结肠癌的严重风险相结合 与昼夜节律的去周期化和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， 调节肥大细胞和炎症。酒精喂养的小鼠，其昼夜节律是 由于光/暗周期的慢性转变而被破坏，发展出明显的肠道和结肠炎症， 导致扩大的有丝分裂增殖区和隐窝延长。我们假设酒精和 昼夜节律的去周期化协同作用，增加炎症和对 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：自发性地 结肠和回肠末端出现良性息肉。在目标1中，我们将确定酒精在多大程度上 协同中枢和外周昼夜节律的环境去极化， 光/暗转换和食物限制导致炎症，加重息肉病和促进CRC。的作用 在这个过程中肥大细胞和T细胞将通过遗传和药理学干预来解决。在Aim中 2，我们将使用遗传方法来确定免疫细胞的昼夜节律破坏在免疫系统中起着重要作用。 在酒精诱导的结肠癌的病理生理学中具有重要作用。我们将通过骨骼产生 骨髓嵌合体小鼠容易患息肉病，并且还表达显性负时钟 免疫区的突变体拟议的研究作为一种潜在的模型具有重要意义， 我们的研究结果将提供新的证据， 癌症预防和靶向治疗的范例。 相关性（参见说明）： 酒精在一部分人中促进癌症的发展/进展;然而，尚不清楚是什么原因。 因素赋予易感性。确定昼夜节律紊乱是一种诱发因素， 癌症发展/进展可能导致新的预防策略或治疗策略（即， 时间生物学疗法和/或益生菌或益生元）用于酒精诱导的癌症。