Role of Alcohol and Circadian Disruption in Inflammation and Colon Cancer

饮酒会导致严重的健康问题，包括结直肠癌(CRC)。然而，准确的 乙醇致癌的机制(S)仍不清楚，因为乙醇本身不是一种 致癌物质。昼夜节律紊乱是酗酒者的常见特征。流行病学研究表明 非传统的工作时间安排(例如，倒班工作)增加了患癌症的风险。这个项目的总体目标是 该项目旨在确定饮酒与结肠癌的严重风险相结合。 与昼夜节律的去同步化，并揭示潜在的细胞免疫机制。 我们有证据表明炎症导致息肉病，肥大细胞协调炎症，以及 Tregs对肥大细胞和炎症的调节。酒精喂养的小鼠的昼夜节律是 被光/暗周期的慢性转换扰乱，出现了明显的肠道和结肠炎， 导致有丝分裂增殖区扩大和隐窝延长。我们假设酒精和 昼夜节律的去同步化协同作用增加炎症和易感性 结肠癌。在这里，我们建议在一种新的小鼠模型中检验这一假设：自发的小鼠 在他们的结肠和回肠远端发展为良性息肉。在目标1中，我们将确定酒精在何种程度上 通过与中枢和外周昼夜节律的环境去同步化协同作用 明/暗转换和食物限制会引起炎症，加剧息肉病，促进结直肠癌。角色 在这一过程中，肥大细胞和树突状细胞之间的相互作用将通过遗传和药物干预来解决。在AIM 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 在酒精诱导的结肠癌的病理生理学中的重要作用。我们将通过骨骼产生 易患息肉病并表达显性负时钟的骨髓嵌合体小鼠 免疫室里的变种人。拟议的研究作为一种潜在的模型具有重要的相关性 与生活方式有关的人类扰乱了正常的昼夜节律组织。我们的发现将证明新的 癌症预防和靶向治疗的范例。 相关性(请参阅说明)： 酒精促进了一部分人的癌症发生/进展；然而，目前还不清楚是什么 因素(S)赋予易感性。发现昼夜节律紊乱是高血压的诱因 癌症的发展/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/或益生素或益生素)治疗酒精诱发的癌症。

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.