S-adenosylmethionine treatment in alcoholic cirrhosis

S-腺苷甲硫氨酸治疗酒精性肝硬化

基本信息

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
项目类别：
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

项目摘要

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.

项目概要酒精性肝硬化是美国发病和死亡的主要原因之一。发病机制是肝脏甲硫氨酸腺苷转移酶 1A (MAT1A) 表达减少，导致肝脏 S-腺苷甲硫氨酸 (SAMe) 水平降低。不利的细胞内后果，包括促进免疫细胞中的炎症级联反应，例如巨噬细胞受到脂多糖（LPS）、氧化应激和内质网（ER）应激的影响。有大量临床前证据支持 SAMe 在酒精性肝病中的应用，但使用的人体试验 SAMe 在酒精性肝硬化中的疗效尚未提供明确的证据。西班牙进行的一项大型试验。其中一位联合研究人员（José Mato 博士）展示了 SAMe 治疗（1200 毫克，分次服用，为期两年）降低了少饮酒晚期肝硬化患者的死亡率，但这是作为事后分析进行的，并没有在美国进行的一项较短（六个月）的试验结果是否定的，但退出率较高。非常高，需要禁欲才能继续试验，这可能掩盖了 SAMe 效果因为安慰剂组有显着改善可能是由于禁欲。该应用涉及两个。美国学术中心（洛杉矶雪松西奈医疗中心和印第安纳大学 Hospital）、西班牙研究机构（CIC bioGUNE）和NIAAA壁内肝脏研究科学家（Bin博士）高）在酒精性肝硬化患者中检查 SAMe 我们提出了一种随机双盲安慰剂。确定 SAMe 对酒精性肝硬化患者的疗效及其机制效应的对照试验此外，我们的目标是在现实世界中鼓励但不要求禁欲。 SAMe 的潜在机制，并使用新的代谢组学来跟踪治疗反应并检查是否基线代谢组学概况与 SAMe 反应相关，提出了两个具体目标：目标 1：我们。将在 SAMe 之间进行一项随机双盲安慰剂对照研究（1,200 毫克/天，分两次给药）剂量）和安慰剂，在酒精性肝硬化患者（儿童 A 级和 B 级）中治疗 24 个月。主要终点是组间任何原因的死亡率。关键的次要终点是肠道通透性、血清内毒素、免疫细胞活化标志物和肝脏特异性的变化使用液相色谱-质谱 (LC-MS) 和 NMR 进行补充代谢组学。基线光谱和试验结束时的核磁共振将评估对治疗的反应以及是否某些概况预测对 SAMe 的反应目标 2：我们将确定 SAMe 治疗对氧化应激的影响，和 ER 应激诱导的线粒体 DNA 和细胞色素 P450 2E1 富集微粒。是新颖的并且与未满足需求的研究领域相关，该领域没有经过证实的有效治疗方法。此外，我们的建议可能会揭示 SAMe 在酒精性肝硬化和代谢组学在这些患者的个性化治疗中的应用。