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Abnormal Food Timing and Circadian Dyssynchrony in Alcohol Induced Colon Carcinogenesis

酒精诱发结肠癌中的异常进食时间和昼夜节律不同步

基本信息

批准号：
10451641
负责人：
Faraz Bishehsari
金额：
$ 18.9万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-10 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10451641
关键词：
Address Admission activity Alcohol consumption Alcohols Animal Experiments Animal Model Animals Apoptosis Area Biological Rhythm Bioperiodicity Brain Calories Cancer Etiology Cancerous Cells Chronic Chronic Disease Circadian Dysregulation Circadian Rhythms Collaborations Colon Colon Carcinoma Colon Injury Colorectal Cancer Consumption Cross-Over Trials Data Eating Food Gastrointestinal tract structure Gene Expression Genes Genetic Predisposition to Disease Habits Homeostasis Hour Human Immigration Immune Immune system Individual Inflammation Inflammatory Inherited Intake Intervention Intestinal Mucosa Intestines Knowledge Lead Lesion Life Style Light Link Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Measurement Measures Mediating Melatonin Modernization Mucositis Mucous Membrane Neoplastic Processes Oral mucous membrane structure Organ Outcome Pathogenesis Pathologic Pathology Pathway interactions Pattern Peripheral Play Precancerous Polyp Predisposition Process Randomized Recording of previous events Regulatory T-Lymphocyte Research Risk Risk Factors Role Salivary Sampling Scientist Sigmoid colon Sigmoidoscopy Sleep Societies Testing Therapeutic Therapeutic Intervention Time Tissues Toxic effect Translating Tubular Adenoma Woman adenoma alcohol effect alcohol intervention cancer risk carcinogenesis circadian circadian pacemaker cofactor colon carcinogenesis colorectal cancer risk colorectal cancer treatment comparative epidemiology study feeding food consumption gut inflammation high risk inflammatory marker men microbiota microbiota profiles mortality mouse model neutrophil novel polyposis preventive intervention recruit risk stratification tissue injury transcriptome sequencing tumor tumorigenic

项目摘要

Abstract Colorectal cancer (CRC) is the second leading cause of cancer mortality in the US. CRC's risk is closely linked to the modern lifestyle. Alcohol is commonly used in our society and is an established risk factor for both pre-cancerous (polyp) and cancerous lesions of the colon. However this knowledge has not been translated to our current risk stratifications for CRC as the process of alcohol-induced carcinogenesis is not predictable. Mucosal inflammation is a well-established mechanism that mediates the effect of alcohol induced tissue injury in the intestine. Inflammation also plays a crucial role in pathogenesis of CRC. Factors that promote a pro-tumorigenic inflammatory state in the setting of alcohol are unknown. Since CRC occurs only in a small subset of alcohol users, alcohol alone may not be sufficient to start the neoplastic process and additional cofactors are required. One such factor is circadian dysrhythmia that is another modern lifestyle habit, shown to be associated with an increased risk of CRC. Further, we have shown that disruption of circadian rhythm exacerbates alcohol-induced intestinal inflammation. We hypothesize that altered circadian rhythms due to “wrong-time” eating (abnormal eating) are an important determinant in alcohol induced intestinal mucosal inflammation and carcinogenesis. Our preliminary data supports our hypothesis and shows that abnormal eating patterns accelerate alcohol-induced polyposis in a mouse model of CRC. In Aim 1, we will establish the inflammatory profiles associated with alcohol ± abnormal eating patterns in the tissues collected from our animal experiments. Here, we establish a cancer-promoting inflammatory state in the colon, determined by RNA-seq and calibrated by immunostaining, linked to alcohol or abnormal eating patterns or their combination. We will then determine the effect of alcohol ± delayed eating patterns (4 conditions) in humans on central and peripheral circadian rhythms in Aim 2, and colon carcinogenesis and mucosal markers in Aim 3. After each intervention, subjects will undergo (1) assessment of central circadian rhythm measured by the dim light melatonin onset (DLMO); (2) assessment of intestinal circadian rhythm measured by clock gene expression in buccal mucosal cells; and (3) sigmoidoscopy sampling of the colon mucosa to assess inflammatory and carcinogenesis markers as well as microbiota. This proposal will identify delayed eating as a promoting factor for alcohol-induced colon injury leading to carcinogenesis, and will provide a paradigm shift in our understanding of the mechanisms underlying alcohol cancer promoting effects, as well as risk stratification of alcohol drinkers.

摘要结直肠癌（CRC）是美国癌症死亡率的第二大原因。CRC的风险是与现代生活方式紧密相连。酒精在我们的社会中被普遍使用，是一个既定的风险因素用于结肠癌前病变（息肉）和癌性病变。然而，这些知识并没有转化为我们目前对CRC的风险分层，因为酒精诱导的致癌过程不是可预测的。粘膜炎症是一种公认的机制，它介导酒精诱导的炎症反应。肠道组织损伤炎症在CRC的发病机制中也起着至关重要的作用。的因素在酒精环境中促进促肿瘤发生的炎症状态是未知的。由于CRC仅在酒精使用者的一小部分，酒精本身可能不足以启动肿瘤过程，需要额外的辅因子。其中一个因素是昼夜节律紊乱，这是另一种现代生活方式习惯，显示与CRC风险增加有关。此外，我们已经表明，昼夜节律加剧了酒精诱导的肠道炎症。我们假设昼夜节律的改变由于“错误时间”进食（异常进食）引起的节律是酒精诱导的肠粘膜炎症和癌变。我们的初步数据支持我们的假设，在结直肠癌小鼠模型中，不正常的饮食模式会加速酒精诱导的息肉病。在目标1中，我们在收集的组织中建立与酒精±异常饮食模式相关的炎症特征从我们的动物实验。在这里，我们在结肠中建立了一种促癌炎症状态，通过RNA-seq确定并通过免疫染色校准，与酒精或异常饮食模式相关，他们的组合。然后，我们将确定酒精±延迟进食模式（4种情况）对人类中枢和外周昼夜节律的目标2，结肠癌和粘膜标志物目标3。每次干预后，受试者将接受（1）测量的中枢昼夜节律评估通过暗光褪黑激素起效时间（DLMO）测定肠道昼夜节律颊粘膜细胞中的基因表达;和（3）结肠粘膜的乙状结肠镜取样以评估炎症和致癌标记物以及微生物群。该提案将延迟进食确定为酒精诱导的结肠损伤导致致癌的促进因素，并将提供一个范式转变，我们对酒精促进癌症作用的机制的理解，以及风险分层酗酒者。