Extracellular Matrix Regulates Hepatic Stellate Cell Activation and Fibrosis

细胞外基质调节肝星状细胞活化和纤维化

• 批准号: 9753207
• 负责人: EKIHIRO SEKI
• 金额: $ 39.38万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753207
• 关键词: 3' Untranslated Regions; 4-methylumbelliferone; Binding; Binding Sites; Biological; Biological Process; Blood; Brain; CD44 gene; Cause of Death; Cholestasis; Cirrhosis; Collagen; Computer Simulation; Data; Deposition; Development; Disease; Disease Progression; Enzymes; Extracellular Matrix; Fibronectins; Fibrosis; Genes; Genetic Transcription; Grant; HAS2 gene; HAS3 gene; Heart; Hepatic Stellate Cell; Hepatitis B; Hepatitis C; Human; Hyaluronan; Hyaluronic Acid; Hyaluronic Acid Binding; Hyaluronidase; In Vitro; Infection; Inflammation; Injury; Intervention; Joints; Kidney; Knock-out; Knockout Mice; Liver; Liver Cirrhosis; Liver Fibrosis; Lung; Mediating; Medical; MicroRNAs; Modeling; Molecular; Molecular Weight; Mus; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Post-Transcriptional Regulation; Production; Promoter Regions; Publications; Pulmonary Fibrosis; Reactive Oxygen Species; Role; Signal Transduction; Source; TLR4 gene; Testing; Tissue Sample; Tissues; Toll-like receptors; Toxin; Transcriptional Regulation; Transforming Growth Factor beta; Transgenic Organisms; WT1 gene; base; chronic liver disease; curative treatments; gain of function; human tissue; hyaluronan synthase 1; in vivo; inhibitor/antagonist; liver development; liver inflammation; liver transplantation; migration; nonalcoholic steatohepatitis; problem drinker; protective effect; receptor; therapeutic evaluation

Project Summary Liver fibrosis is the consequence of chronic liver diseases, such as hepatitis B and C infection, and alcoholic and non-alcoholic steatohepatitis (NASH). Currently there is no effective anti-fibrotic agent for liver cirrhosis. Therefore, the unmet medical needs for liver fibrosis/cirrhosis are significant. Liver inflammation is a crucial mechanism for activation of hepatic stellate cell (HSCs) and liver fibrosis. Activated HSCs produce extracellular matrix (ECM) including collagen, fibronectin, and hyaluronic acids (HA). Endogenous HA have been implicated in the disease progression of lungs, kidneys, joints, heart, and brain. In the liver, patients with liver cirrhosis show elevated HA levels in the blood. However, the biological functions of endogenous HA produced in liver fibrosis have not been determined. HA are produced in high molecular weight forms (HMW; MW>1000kDa) by hyaluronan synthase (HAS) 1-3. In the setting of inflammation, HA are degraded into low molecular weight (LMW) forms (MW~100-300kDa). LMW-HA exacerbates tissue injury and inflammation through binding to its receptors, CD44 and TLR4. The objective of this study is to determine the biological functions of endogenous HA and its downstream effector pathway in HSC activation and in liver fibrosis. Based on previous publications and our preliminary studies, we hypothesize that HAS2-mediated HSC-derived HA and HA's downstream effector pathways promote HSC activation and liver fibrosis. Moreover, we further hypothesize that by targeting HA a new interventional strategy for treating liver fibrosis can be developed. To test our hypotheses, we will investigate if HAS2-mediated HA production in HSCs promotes liver fibrosis through loss- and gain-of-function approaches using HSC-specific Has2 knockout (Has2∆HSC) mice and HAS2 transgenic (ASMA-HAS2 Tg) mice. We will also use human tissue samples to examine HSCs as the source of HAS2 and HA in human cirrhotic livers (Aim 1). We will investigate the transcriptional and posttranscriptional regulation of HAS2 expression in HSCs as the molecular mechanisms of dysregulated HAS2 expression in liver fibrosis (Aim 2). We will then investigate the role of Notch1 signaling as the HA's downstream effector pathway for HSC activation and liver fibrosis (Aim 3). Finally, we will examine interventional potential of blocking HA synthesis for treating liver fibrosis (Aim 4).

项目总结