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Methionine Adenosyltransferase as a Therapeutic Target for Liver Fibrosis

蛋氨酸腺苷转移酶作为肝纤维化的治疗靶点

基本信息

批准号：
8475416
负责人：
Komal Ramani
金额：
$ 22.3万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-07 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8475416
关键词：
Address Alcohol consumption Anabolism Animal Model Award Biliary Binding Biochemical Biological Blood Platelets Catalytic Domain Cell Line Development Dose Elements Enzymes Event Extrahepatic Fibrosis Gene Expression Gene Silencing Genes Growth Factor Hepatic Stellate Cell Hepatitis Hepatocyte Growth Factor Human In Vitro Isoenzymes Leptin Ligation Liver Liver Cirrhosis Liver Fibrosis Malignant - descriptor Malignant neoplasm of liver Mammalian Cell Methionine Methylation Modeling Molecular Molecular Biology Techniques Obstruction Outcome PPAR gamma PPAR-beta Pathway interactions Peroxisome Proliferator-Activated Receptors Phase Platelet-Derived Growth Factor Play Polyamines Primary carcinoma of the liver cells Process Rattus Research Personnel Role S-Adenosylmethionine Signal Transduction Transferase Transferase Gene Work bile duct cancer cell cell growth chronic liver disease in vivo inhibitor/antagonist insight interest liver cell proliferation liver injury methionine adenosyltransferase novel novel therapeutic intervention promoter research study response therapeutic development therapeutic target treatment strategy

项目摘要

Hepatic fibrosis is an outcome of many chronic liver diseases such as alcohol consumption, biliary obstruction and hepatitis. Prolonged liver injury triggers activation of hepatic stellate cells (HSC) and leads to modulation of key transcriptional regulators. Methionine adenosyl transferases (MAT) catalyze the formation of the principle biological methyl donor, S-adenosylmethionine (SAMe). Two genes, MAT2A and MAT2B, are known to be strongly associated with liver cell proliferation and malignant degeneration. In the K99 phase, we showed that MAT2A and MAT2B genes are induced during HSC activation both in vitro and in vivo, This is associated with a decrease in MAT activity and SAMe levels. Gene silencing studies showed that these genes are important for HSC activation. The MAT2A gene is transcriptionally regulated in normal, differentiated HSCs by binding of peroxisome proliferator activated receptor (PPAR-gamma) to the MAT2A promoter. During HSC activation, there is decreased activity and expression of PPAR-gamma and its regulatory control over MAT2A is abolished, leading to increased expression of MAT2A. We also show that HSC activation is associated with increased binding of PPAR-beta to the MAT2A promoter and silencing PPAR-beta blocks MAT2A induction in activated HSCs. In the ROO phase ofthis award, we will use biochemical and molecular biology techniques to address four specific aims: 1) To evaluate whether MAT genes are required for in vivo HSC activation in rat models of liver fibrosis and study their interplay with molecular signals in HSCs from fibrotic liver, 2) to examine whether known pro-fibrogenic factors, leptin and platelet-derived growrth factor (PDGF) can influence MAT gene expression in rat HSCs and whether SAMe and MTA can block this response, 3) to evaluate the expression of MAT genes in human HSC cell lines during activation in response to pro-fibrogenic signals, leptin and platelet-derived growth factor (PDGF) and further'understand these mechanisms in HSCs isolated from human liver, and 4) to establish'molecular mechanisms for regulatory control of MAT2A and MAT2B expression in human HSCs. My long term plan is to establish myself as an independent Investigator in the field of human liver fibrosis and cirrhosis.

肝纤维化是许多慢性肝脏疾病如饮酒、胆道疾病、糖尿病等的结果。梗阻和肝炎。长期肝损伤会触发肝星状细胞（HSC）的激活并导致关键转录调节因子的调节。甲基腺苷转移酶（MAT）催化主要生物甲基供体S-腺苷甲硫氨酸（SAMe）。两个基因，MAT 2A和MAT 2B，已知与肝细胞增殖和恶性变性密切相关。在K99阶段，我们发现，在体外和体内HSC活化过程中，MAT 2A和MAT 2B基因都被诱导，与MAT活性和SAMe水平的降低有关。基因沉默研究表明，基因对于HSC活化是重要的。MAT 2A基因在正常人中受转录调节，通过过氧化物酶体增殖物激活受体（PPAR-gamma）与MAT 2A的结合分化HSC 启动子在HSC活化过程中，PPAR-γ及其受体的活性和表达降低。对MAT 2A的调节控制被取消，导致MAT 2A的表达增加。我们也证明了 HSC活化与PPAR-beta与MAT 2A启动子结合增加和沉默相关 PPAR-beta阻断活化HSC中的MAT 2A诱导。在本奖项的ROO阶段，我们将使用生物化学和分子生物学技术，以解决四个具体目标：1）评估是否MAT 基因是肝纤维化大鼠模型中体内HSC活化所必需的， 2）检查已知的促纤维化因子瘦素和纤维化因子是否存在于来自纤维化肝的HSC中，血小板源性生长因子（PDGF）可影响大鼠HSC中MAT基因的表达， MTA可阻断这种反应; 3）检测人HSC细胞系中MAT基因的表达在响应促纤维化信号的活化过程中，瘦素和血小板衍生生长因子（PDGF）以及进一步了解从人肝脏分离的HSC中的这些机制，以及4）建立“分子在人HSC中调控MAT 2A和MAT 2B表达的机制。我的长期计划是确立自己作为人类肝纤维化和肝硬化领域的独立研究者的地位。