S-adenosylmethionine treatment in alcoholic cirrhosis

S-腺苷甲硫氨酸治疗酒精性肝硬化

• 批准号: 10247836
• 负责人: Suthat Liangpunsakul
• 金额: $ 35.3万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247836
• 关键词: Abstinence; Alcohol abuse; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcoholic steatohepatitis; Alcohols; Area; Biological; Biological Markers; CYP2E1 gene; Catalytic Domain; Cells; Child; Cirrhosis; Complex; Complication; DNA; Data; Diglycerides; Disease; Dose; Double-Blind Method; Dropout; Endotoxemia; Endotoxins; Enzymes; Fatty Acids; Fibrosis; Genes; Health; Hepatic; Human; Immune; Immunologic Markers; Indiana; Inflammation; Inflammatory; Injury; Intestinal permeability; Knock-out; Lead; Lipopolysaccharides; Liver; Liver diseases; Los Angeles; Mammals; Medical center; Messenger RNA; Methionine; Mitochondria; Morbidity - disease rate; NMR Spectroscopy; National Institute on Alcohol Abuse and Alcoholism; Oral; Oral Administration; Oxidative Stress; Oxidative Stress Induction; Pathogenesis; Pathologic; Patients; Placebos; Process; Proteins; Public Health; Randomized; Research; Research Design; Research Institute; Research Personnel; Risk; Risk Factors; Role; S-Adenosylmethionine; Sample Size; Scientist; Secondary to; Series; Serum; Spain; Supplementation; Techniques; Triglycerides; United States; University Hospitals; Violence; dimer; double-blind placebo controlled trial; effective therapy; endoplasmic reticulum stress; extracellular vesicles; human disease; immune activation; improved; inclusion criteria; insight; liquid chromatography mass spectrometry; macrophage; metabolic phenotype; metabolomics; methionine adenosyltransferase; mortality; novel; novel strategies; personalized medicine; placebo controlled study; placebo group; pre-clinical; predicting response; primary endpoint; problem drinker; randomized placebo controlled study; response; secondary endpoint; survival outcome; treatment response

Project Summary Alcoholic cirrhosis is a leading cause of morbidity and mortality in the US. One of the key drivers in its pathogenesis is the reduction in hepatic methionine adenosyltransferase 1A (MAT1A) expression resulting in the reduction in hepatic S-adenosylmethionine (SAMe) levels. The reduction in SAMe level leads to several adverse intracellular consequences, which include promoting the inflammatory cascades in immune cells such as macrophages by lipopolysaccharides (LPS), oxidative stress and endoplasmic reticulum (ER) stress. There is extensive preclinical evidence that support the use of SAMe in alcoholic liver disease but human trials using SAMe in alcoholic cirrhosis have not provided clear evidence of efficacy. One large trial conducted in Spain by one of the co-investigators (Dr. José Mato) showed SAMe treatment (1200 mg in divided doses for two years) reduced the mortality of less advanced alcoholic cirrhotics but this was done as a post-hoc analysis and no mechanism was investigated. A shorter (six months) trial done in the U.S. was negative but the dropout rate was very high and abstinence was required to stay in the trial, which may have obscured the SAMe effect since placebo group had marked improvement likely due to abstinence. This application involves two academic centers in the United States (Cedars-Sinai Medical Center in Los Angeles and Indiana University Hospital), a research institute in Spain (CIC bioGUNE), and NIAAA intramural liver research scientist (Dr. Bin Gao) to examine SAMe in humans with alcoholic cirrhosis. We propose a randomized double-blind placebo controlled trial to determine the efficacy of SAMe and its mechanistic effects in patients with alcoholic cirrhosis in the real world setting by encouraging but not requiring abstinence. In addition, we aim to investigate the underlying mechanism(s) of SAMe and use novel metabolomics to follow response to treatment and examine if baseline metabolomics profiles correlate with response to SAMe. Two specific aims are proposed: Aim 1: we will perform a randomized double-blind placebo controlled study between SAMe (1,200 mg/day given in two divided dose) and placebo, in patients with alcoholic cirrhosis (Child class A and B) for 24 months. The primary endpoint will be the mortality of any causes between groups. The key secondary endpoints are the changes in intestinal permeability, serum endotoxin, markers of immune cell activations, and liver-specific mortality. Complementary metabolomics using liquid-chromatography-mass spectrometry (LC-MS) and NMR spectroscopy at baseline and NMR at the end of the trial will assess response to treatment and whether certain profiles predict response to SAMe. Aim 2: we will determine the effect of SAMe treatment on oxidative stress, and ER-stress induced mitochondrial DNA and cytochrome P450 2E1 enriched microparticles. Our application is novel and relevant to an un-met need area of research where no proven effective treatments are available. In addition, our proposal may unveil novel mechanistic insights on the effect of SAMe in alcoholic cirrhosis and the use of metabolomics in personalized treatment of these patients.

项目摘要 酒精性肝硬化是美国发病率和死亡率的主要原因。它的关键驱动力之一 发病机理是甲二氨酸腺苷转移酶1a（MAT1A）表达的降低，导致 肝素S-腺苷甲硫代氨酸（相同）水平的降低。相同级别的降低导致几个 不良细胞内后果，其中包括促进免疫细胞中的炎性级联反应 作为脂多糖（LPS）的巨噬细胞，氧化应激和内质网应激。那里 是广泛的临床前证据，支持在酒精性肝病中使用相同的证据，但人类试验使用 酒精性肝硬化中的同样尚未提供明确的效率证据。一项在西班牙进行的大型试验 其中一位共同评估剂（JoséMato博士）显示出相同的治疗方法（两年的剂量为1200 mg） 降低了不太先进的酒精性肝硬化的死亡率，但这是作为事后分析进行的，没有 调查了机制。在美国进行的较短（六个月）的试验是负面的，但辍学率 很高，需要禁欲才能留在审判中，这可能掩盖了相同的效果 由于安慰剂组明显改善，因此可能由于禁欲而有所改善。该应用涉及两个 美国的学术中心（洛杉矶和印第安纳大学的Cedars-Sinai Medical Center 医院），西班牙的研究所（CIC Biogune）和NIAAA壁内研究科学家（Bin博士 GAO）在患有酒精性肝硬化的人类中检查。我们提出了一个随机的双盲安慰剂 对照试验确定同一效果及其机械作用在酒精性肝硬化患者中的有效性 在现实世界中，通过鼓励但不需要戒酒来设置。此外，我们旨在调查 相同的基本机制，并使用新型代谢组学遵循治疗和检查的反应 基线代谢组学轮廓与对响应的响应相关。提出了两个具体目标：目标1：我们 将执行一项随机的双盲安慰剂对照研究（在两次中给出的1,200 mg/天） 剂量）和安慰剂，在酒精性肝硬化患者（儿童A和B）中持续24个月。这 主要终点将是组之间任何原因的死亡率。关键的次要终点是 肠道渗透性，血清内毒素，免疫细胞活化标志和肝脏特异性的变化的变化 死亡。使用液相染料量质谱法（LC-MS）和NMR的补充代谢组学 基线和试验结束时NMR的光谱法将评估对治疗的反应以及是否某些 概况预测对同一的响应。目标2：我们将确定相同治疗对氧化应激的影响， ER应激诱导的线粒体DNA和细胞色素P450 2E1富含微粒。我们的申请 是新颖的，与未经证实有效治疗的研究领域有关。 此外，我们的提议可能会揭示出对酒精性肝硬化和饮酒中效果的新机械见解 代谢组学在对这些患者的个性化治疗中的使用。