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).

项目摘要 肝纤维化是慢性肝病的结果，例如乙型肝炎和C感染，以及 酒精和非酒精性脂肪性肝炎（NASH）。目前尚无有效的抗纤维化剂的肝脏 肝硬化。因此，对肝纤维化/肝硬化的未满足医学需求很大。 肝感染是激活肝星状细胞（HSC）和肝纤维化的关键机制。 活化的HSC产生细胞外基质（ECM），包括胶原蛋白，纤连蛋白和氢酸（HA）。 肺，肾脏，关节，心脏和大脑的疾病进展中隐含了内源性HA。 肝脏肝硬化患者的血液中HA水平升高。但是， 尚未确定在肝纤维化中产生的内源性HA。 HA以高分子产生 透明质酸合酶（HAS）1-3的重量形式（HMW； MW> 1000kDa）。在炎症的情况下，HA是 降解为低分子量（LMW）形式（MW〜100-300KDA）。 LMW-HA加剧组织损伤和 通过与其受体CD44和TLR4结合的炎症。 这项研究的目的是确定内源性HA及其ITS的生物学功能 HSC激活和肝纤维化中的下游效应途径。根据以前的出版物和 我们的初步研究，我们假设HAS2介导的HSC衍生的HA和HA的下游 效应途径促进HSC激活和肝纤维化。此外，我们进一步假设 可以开发针对HA治疗肝纤维化的新介入策略。 为了检验我们的假设，我们将研究HAS2介导的HSC中HA的产生是否促进肝脏 使用HSC特异性HAS2敲除（HAS2ΔHSC）小鼠通过损失和功能获取方法的纤维化和 HAS2转基因（ASMA-HAS2 TG）小鼠。我们还将使用人体组织样品来检查HSC作为 人类肝硬化生活中的HAS2和HA的来源（AIM 1）。我们将研究转录和 HSC中HAS2表达的转录后调节作为失调的分子机制 肝纤维化中的HAS2表达（AIM 2）。然后，我们将研究Notch1信号作为HA的作用 HSC激活和肝纤维化的下游效应途径（AIM 3）。最后，我们将检查 阻断HA合成以治疗肝纤维化的介入潜力（AIM 4）。