Full Project II: Novel Risk Factors and Disease Associations of Liver Cancer in Guam

完整项目 II：关岛肝癌的新危险因素和疾病关联

• 批准号: 10490855
• 负责人: BRENDA Y HERNANDEZ
• 金额: $ 10.6万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490855
• 关键词: 16S ribosomal RNA sequencing; Address; Alcohols; Areca; Bacterial Genes; Biological Markers; Blood; Case-Control Studies; Chronic Hepatitis C; Circadian Rhythms; Collaborations; Data; Diabetes Mellitus; Disease; Early Intervention; Etiology; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Genes; Glucose; Guam; Hepatitis C virus; High Prevalence; Incidence; Link; Lipids; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Mastication; Measures; Mediating; Metabolic; Metabolic Diseases; Native-Born; Nuts; Obesity; Oral; Oral cavity; Oral health; Pacific Islands; Pathogenicity; Patient Self-Report; Patients; Pattern; Periodontal Diseases; Population; Primary carcinoma of the liver cells; Questionnaires; Research; Risk; Risk Factors; Role; Sampling; Severities; Sleep; Sleep Apnea Syndromes; Sleep disturbances; Snoring; Stratification; United States; Viral hepatitis; cancer health disparity; chronic liver disease; circadian pacemaker; clinical examination; commensal bacteria; cryptochrome; dysbiosis; health equity; insulin signaling; mRNA Expression; microbial; mortality; non-alcoholic fatty liver disease; novel; novel strategies; oral microbiome; preventive intervention; secondary outcome; sleep abnormalities; sleep quantity

PROJECT SUMMARY/ABSTRACT The US territory of Guam has a staggeringly high burden of liver cancer with incidence and mortality more than twice that of overall rates in the United States (US) where rates have nearly tripled over the past three decades. Excess risk is most prominent among CHamorus who are the native people of Guam, comprising 42% of the population. Hepatocellular carcinoma (HCC), the primary form of liver cancer, develops entirely within the context of progressive chronic liver disease (CLD) characterized by advancing levels of fibrosis. Thus, there is an urgent need to understand the etiology of progressive CLD in CHamorus and to identify novel strategies and targets for prevention and early intervention. Our proposed research will address whether oral dysbiosis and sleep/circadian rhythm disturbance contribute to liver fibrosis through glucose and lipid dysmetabolism and the potential modifying effect of other exposures. We propose a case-control study of 300 liver fibrosis cases and 300 matched controls among CHamorus in Guam. Liver fibrosis, a well-established precursor of liver cancer, as well as liver steatosis as a secondary outcome, will be measured by transient elastrography (Fibroscan). The Specific Aims of Full Project II are to: 1) Evaluate the association of oral dysbiosis with liver fibrosis and steatosis. Oral dysbiosis will be defined as deleterious patterns of the oral microbiome and/or the presence of periodontal disease. We will perform bacterial 16S rRNA sequencing to measure oral bacterial diversity and composition. We will determine periodontal disease by clinical examination and self-report. The association between oral dysbiosis and liver fibrosis, with or without stratification by steatosis grades, will be evaluated; the potential modifying effects of other exposures (e.g., betel nut chewing, viral hepatitis, alcohol) and the mediating effects of glucose and lipid dysmetabolism will be assessed. We hypothesize that having moderate to severe liver fibrosis is associated with: 1a) reduced oral microbial diversity, enriched pathogenic and depleted commensal bacteria, and aberrations in insulin- signaling bacterial genes; 1b) the presence and severity of periodontal disease; and 1c) oral dysbiosis through and independently of glucose/lipid dysmetabolism. 2) Evaluate the associations of sleep (quantity and quality) and circulating Mrna expression levels of circadian clock genes with liver fibrosis and steatosis. We will determine sleep duration and quality using validated questionnaires and analyze the expression of the period (Per1, Per2, Per3) and cryptochrome (Cry2) genes in blood as a biomarker of circadian rhythm. We hypothesize that liver fibrosis is associated with: 2a) short sleep duration and sleep apnea; 2b) reduced expression of the clock genes; and 2c) sleep/circadian rhythm disturbances through and independently of glucose/lipid dysmetabolism.

项目概要/摘要 美国领土关岛的肝癌负担高得惊人，发病率和死亡率超过 是美国总体利率的两倍，在过去三十年里，美国的利率几乎增加了两倍。 过度风险在关岛原住民查莫罗人中最为突出，占人口的 42%。 人口。肝细胞癌 (HCC) 是肝癌的主要形式，完全在这种背景下发展 以纤维化水平升高为特征的进行性慢性肝病（CLD）。因此，有一个紧急的 需要了解查莫鲁人进行性慢性肺病的病因，并确定治疗的新策略和目标 预防和早期干预。我们提出的研究将解决口腔生态失调是否与睡眠/昼夜节律有关 节律紊乱通过葡萄糖和脂质代谢障碍导致肝纤维化，并且可能 修改其他曝光的效果。我们建议对 300 例肝纤维化病例和 300 例匹配的病例进行病例对照研究 控制关岛的查莫罗人。肝纤维化是肝癌的既定前兆，同时也是肝癌的前兆 脂肪变性作为次要结果，将通过瞬时弹性成像（Fibroscan）进行测量。 完整项目 II 的具体目标是： 1) 评估口腔生态失调与肝纤维化和脂肪变性的关联。口腔生态失调定义为 口腔微生物组的有害模式和/或牙周病的存在。我们将进行细菌 16S rRNA 测序可测量口腔细菌多样性和组成。我们将确定牙周 通过临床检查和自我报告来诊断疾病。口腔生态失调与肝纤维化之间的关联，或 不按脂肪变性等级分层，将进行评估；其他暴露的潜在改变效应 （例如，咀嚼槟榔、病毒性肝炎、酒精）以及葡萄糖和脂质代谢异常的中介作用 将被评估。我们假设中度至重度肝纤维化与： 1a) 减少 口腔微生物多样性、致病菌丰富和共生菌枯竭以及胰岛素异常 细菌基因信号传导； 1b) 牙周病的存在及其严重程度； 1c) 口腔生态失调 并且独立于葡萄糖/脂质代谢异常。 2) 评估睡眠（数量和质量）与昼夜节律循环Mrna表达水平的关联 与肝纤维化和脂肪变性相关的时钟基因。我们将使用经过验证的方法确定睡眠持续时间和质量 问卷调查并分析周期（Per1、Per2、Per3）和隐花色素（Cry2）基因的表达 血液作为昼夜节律的生物标志物。我们假设肝纤维化与：2a) 睡眠不足有关 持续时间和睡眠呼吸暂停； 2b) 时钟基因表达减少； 2c) 睡眠/昼夜节律 通过且独立于葡萄糖/脂质代谢异常的紊乱。