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).

项目概要 肝纤维化是慢性肝病的结果，例如乙型和丙型肝炎感染，以及 酒精性和非酒精性脂肪性肝炎（NASH）。目前尚无有效的抗肝纤维化药物 肝硬化。因此，肝纤维化/肝硬化的未满足的医疗需求是巨大的。 肝脏炎症是肝星状细胞（HSC）激活和肝纤维化的重要机制。 激活的 HSC 产生细胞外基质 (ECM)，包括胶原蛋白、纤连蛋白和透明质酸 (HA)。 内源性透明质酸与肺、肾、关节、心脏和大脑的疾病进展有关。在 肝脏，肝硬化患者的血液中HA水平升高。然而，其生物学功能 肝纤维化中产生的内源性HA尚未确定。 HA 是以高分子形式生产的 由乙酰透明质酸合酶 (HAS) 1-3 形成重量形式 (HMW; MW>1000kDa)。在炎症情况下，HA 降解为低分子量（LMW）形式（MW~100-300kDa）。 LMW-HA 加剧组织损伤 通过与其受体 CD44 和 TLR4 结合来抑制炎症。 本研究的目的是确定内源性 HA 的生物学功能及其 HSC 激活和肝纤维化中的下游效应通路。根据之前的出版物和 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 效应通路促进 HSC 激活和肝纤维化。此外，我们进一步假设通过 以HA为靶点，可以开发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 HSC 中 HAS2 介导的 HA 产生是否会促进肝脏功能 使用 HSC 特异性 Has2 敲除 (Has2ΔHSC) 小鼠通过功能丧失和获得功能方法来治疗纤维化 HAS2 转基因 (ASMA-HAS2 Tg) 小鼠。我们还将使用人体组织样本来检查 HSC 作为 人类肝硬化肝脏中 HAS2 和 HA 的来源（目标 1）。我们将研究转录和 HSCs 中 HAS2 表达的转录后调控作为失调的分子机制 肝纤维化中的 HAS2 表达（目标 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通路（目标 3）。最后，我们将检查 阻断 HA 合成治疗肝纤维化的介入潜力（目标 4）。