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

• 批准号: 7660580
• 负责人: Komal Ramani
• 金额: $ 14.53万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660580
• 关键词: Address; Alcohol consumption; Anabolism; Animal Model; Autoimmune Hepatitis; Award; Biliary; Biochemical; Biological; Catalytic Domain; Cell Line; Cells; Chronic; Cirrhosis; Development; Dose; Elements; Enzymes; Event; Extrahepatic; Fibrosis; Gene Expression; Genes; Genome; Growth Factor; Hepatic Stellate Cell; Hepatocyte Growth Factor; Human; In Vitro; Inflammatory; Injury; Isoenzymes; Leptin; Ligation; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Malignant - descriptor; Malignant neoplasm of liver; Mammalian Cell; Mediating; Mentors; Methionine; Methylation; Modeling; Molecular; Molecular Biology Techniques; Obstruction; Outcome; Pathway interactions; Phase; Platelet-Derived Growth Factor; Play; Polyamines; Primary carcinoma of the liver cells; Process; Rattus; Research Personnel; Role; Signal Pathway; Signal Transduction; Transferase; Transferase Gene; Viral; Work; bile duct; cancer cell; cell growth; fibrogenesis; in vivo; inhibitor/antagonist; insight; interest; liver cell proliferation; methionine adenosyltransferase; novel; novel therapeutic intervention; research study; response; therapeutic development; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Project Summary: Hepatic fibrosis is an outcome of many chronic liver diseases, such as viral and autoimmune hepatitis, and of alcohol consumption and biliary obstruction. Prolonged liver injury triggers activation of hepatic stellate cells (HSC) and recruitment of inflammatory cells into the liver. At the molecular level, these changes involve modulation of the expression or activity of key transcriptional regulators of the genome. Methionine adenosyl transferases (MAT) are essential enzymes that catalyze the formation of the principle biological methyl donor, S-adenosylmethionine (SAMe). Two of the MAT genes, MAT2A and MAT2p are known to be strongly associated with liver cell proliferation and malignant degeneration. Recently we discovered that MAT2A and MAT2P genes are essential for proliferation of liver cancer cells mediated by a well known pro-fibrogenic factor, leptin. These novel findings led us to hypothesize that the expression of MAT genes is induced during HSC activation and this may be an important event during fibrogenesis. Thus, we plan to use biochemical and molecular biology techniques to address four specific aims: 1) to evaluate the expression of MAT genes during activation of rat HSCs in vitro and in vivo and to determine whether they are required for activation, 2) to establish whether the metabolites in the MAT signaling pathway, SAMe and methylthioadenosine (MTA) can alter MAT gene expression and HSC activation, 3) to examine whether known pro-fibrogenic factors, leptin and platelet-derived growth factor (PDGF) can influence MAT gene expression in rat HSCs and whether SAMe and MTA can block this response and 4) 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. We will initiate the first two aims during the mentored phase and I will further develop the subsequent aims during the independent phase of the award. My long term plan is to establish myself as an independent investigator in the field of human liver fibrosis and cirrhosis. RELEVANCE (Seeinstructions): The proposed experiments will provide a better understanding of the mechanisms underlying hepatic fibrosis its associated complications and will be useful in the development of therapeutic strategies for treatment of human liver fibrosis.

描述（由申请人提供）：项目概述：肝纤维化是许多慢性肝病的结果，如病毒性肝炎和自身免疫性肝炎，以及饮酒和胆道梗阻。长期的肝损伤触发肝星状细胞（HSC）的活化和炎性细胞向肝脏中的募集。在分子水平上，这些变化涉及基因组的关键转录调节因子的表达或活性的调节。甲硫氨酸腺苷转移酶（MAT）是催化主要生物甲基供体S-腺苷甲硫氨酸（SAMe）形成的必需酶。已知MAT基因中的两个MAT 2A和MAT 2 p与肝细胞增殖和恶性变性密切相关。最近我们发现，MAT 2A和MAT 2 P基因是由众所周知的促纤维化因子瘦素介导的肝癌细胞增殖所必需的。这些新的发现使我们假设MAT基因的表达在HSC活化过程中被诱导，这可能是纤维形成过程中的一个重要事件。因此，我们计划使用生物化学和分子生物学技术来解决四个具体目标：1）评估MAT基因在体外和体内活化大鼠HSC期间的表达，并确定它们是否是活化所需的，2）确定MAT信号传导途径中的代谢物SAMe和甲硫腺苷（MTA）是否可以改变MAT基因表达和HSC活化，3）检查已知的促纤维化因子、瘦素和血小板衍生生长因子（PDGF）是否可以影响大鼠HSC中的MAT基因表达，以及SAMe和MTA是否可以阻断这种应答，以及4）评估在响应促纤维化信号的活化过程中人HSC细胞系中MAT基因的表达，瘦素和血小板源性生长因子（PDGF），并进一步了解从人肝脏分离的HSC中的这些机制。我们将在指导阶段启动前两个目标，我将在该奖项的独立阶段进一步制定后续目标。我的长期计划是建立自己在人类肝纤维化和肝硬化领域的独立调查员。相关性（参见说明）：这些实验将有助于我们更好地理解肝纤维化及其相关并发症的机制，并有助于开发治疗人类肝纤维化的治疗策略。