TTP in alcohol induced liver fibrosis

TTP在酒精性肝纤维化中的作用

• 批准号: 9316397
• 负责人: Narasaiah Kolliputi
• 金额: $ 17.75万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316397
• 关键词: Accounting; Alcohol abuse; Alcohols; Attenuated; Bile Duct Epithelium; Binding Proteins; Cell Adhesion; Cell Differentiation process; Cells; Chemicals; Cirrhosis; Collagen; Collagen Type I; Complement Factor B; Computer Simulation; Country; Data; Deposition; Development; Disease; Down-Regulation; Endothelial Cells; Epithelial Cells; Ethanol; Extracellular Matrix; Fibroblasts; Fibrosis; Goals; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis B; Hydroxyproline; In Vitro; Inflammation Mediators; Injury; Knock-out; Link; Liver; Liver Cirrhosis; Liver Fibrosis; Locomotion; Mediating; Messenger RNA; Morbidity - disease rate; Mus; Myofibroblast; Organ; Outcome Study; Pathology; Pathway interactions; Production; Proteins; Resistance; Role; TIS11 protein; Testing; Tissues; Transforming Growth Factors; base; connective tissue growth factor; cytokine; effective therapy; global health; mRNA Decay; mRNA Expression; mRNA Stability; mortality; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; prevent; problem drinker; protein expression; public health relevance; skin fibrosis; therapeutic development; transdifferentiation

 DESCRIPTION (provided by applicant): Liver fibrosis (LF)/cirrhosis is a major global health problem and one of the leading causes of morbidity and mortality in the world. Alcohol abuse is one of the most common causes of liver fibrosis/cirrhosis in developed Western countries, accounting for more than 50% of cirrhosis cases. At present, there is no effective treatment for LF. Alcoholic liver fibrogenesis evolves from an imbalance between cytokines and hepatic stellate cell (HSC) activation and transdifferentiation into myofibroblasts. Attenuating these profibrotic mechanisms is an important step towards developing new therapeutic interventions for LF. Our long-term goal is to elucidate the regulatory mechanisms in LF pathology as a necessary prerequisite for the development of therapeutic agents that will minimize or reverse fibrosis. CTGF/CCN2 (connective tissue growth factor, CTGF) is a stable, profibrotic protein that promotes HSC adhesion, proliferation, locomotion, and collagen production. In a fibrotic liver, CTGF/CCN2 is produced by HSCs, fibroblasts, myofibroblasts, endothelial cells, and bile duct epithelial cells. CTGF/CCN2 expression promotes LF. CTGF administration significantly upregulates type I collagen synthesis and promotes fibrosis by mediating the ability of transforming growth factor β (TGF-β) to induce excess extracellular matrix (ECM) production. Following stimulation by the fibrotic inflammatory mediator TGF-β, CTGF/CCN2 expression in cultured HSCs is enhanced. Loss of CTGF/CCN2 in fibroblasts results in decreased collagen deposition and resistance to chemically induced skin fibrosis. Knockout of CTGF/CCN2 prevents LF, thus modulation of its activity/expression represents a novel therapeutic target in this disease. However, factors that regulate CTGF/CCN2 mRNA expression and prolonged stability in liver fibrosis are unknown. Tristetraprolin (TTP) is an mRNA-binding protein that destabilizes mRNAs, leading to reduced protein expression. However, the link between TTP expression and stability of CTGF is unknown. TTP is highly expressed only in the liver compared to other tissues; moreover, significant downregulation of TTP is evident in hepatitis B virus (HBV)-associated cirrhosis. However, the role of TTP in controlling the expression of profibrotic CTGF/CCN2 has not been explored. We have developed a novel hypothesis that TTP functions as an mRNA destabilizer of CGF/CCN2 expression and that loss of TTP leads to alcohol-induced LF by hepatic stellate cell (HSC) activation and transdifferentiation into myofibroblasts. To test this hypothesis, the following specific aims are proposed: Aim #1: Define the role of TTP as a negative regulator of CTGF/CCN2 expression and concurrent HSC differentiation by assessing gain/loss of TTP in vitro. Aim #2: To determine whether TTP suppression is critical for alcoholic- induced fibrosis and further examine whether TTP-deficiency exacerbates alcohol-induced fibrosis. The outcome of this study will be a fundamental, ground-breaking understanding of the mechanisms that control the expression of the profibrotic molecule CTGF/CCN2 in alcoholic LF. This will have a significant impact on the development of novel therapies for alcoholic liver fibrosis.

 描述（由申请人提供）：肝纤维化（LF）/肝硬化是一个主要的全球健康问题，也是世界上发病和死亡的主要原因之一。酒精滥用是发达国家肝纤维化/肝硬化的最常见原因之一。西方国家肝硬化病例中，目前尚无有效的治疗方法，酒精性肝纤维化是由细胞因子与肝脏之间的失衡演变而来。星状细胞（HSC）激活并转分化为肌成纤维细胞是开发新的 LF 治疗干预措施的重要一步，我们的长期目标是阐明 LF 病理学的调节机制，这是开发治疗的必要先决条件。 CTGF/CCN2（结缔组织生长因子，CTGF）是一种稳定的促纤维化蛋白，可促进 HSC 粘附，在纤维化肝脏中，CTGF/CCN2 由 HSC、成纤维细胞、内皮细胞和胆管上皮细胞产生，CTGF/CCN2 的表达可显着上调 LF 的合成。通过介导转化生长因子 β (TGF-β) 诱导过量细胞外基质 (ECM) 产生的能力来促进纤维化。受到纤维化炎症介质 TGF-β 的刺激后，培养的 HSC 中 CTGF/CCN2 的表达增强。成纤维细胞中 CTGF/CCN2 的缺失导致胶原蛋白沉积减少，并且敲除 CTGF/CCN2 可防止 LF。其活性/表达的调节代表了该疾病的一个新的治疗靶标，然而，调节 CTGF/CCN2 mRNA 表达和肝纤维化的长期稳定性的因素是。 Tristetraprolin (TTP) 是一种 mRNA 结合蛋白，可破坏 mRNA 的稳定性，从而导致蛋白质表达减少。然而，与其他组织相比，TTP 表达与 CTGF 稳定性之间的联系尚不清楚。在乙型肝炎病毒 (HBV) 相关肝硬化中，TTP 显着下调，但我们尚未探讨 TTP 在控制促纤维化 CTGF/CCN2 表达中的作用。提出了一种新的假设，即 TTP 作为 CGF/CCN2 表达的 mRNA 不稳定剂，并且 TTP 的缺失会导致肝星状细胞 (HSC) 活化和转分化为肌成纤维细胞而导致酒精诱导的 LF。为了检验这一假设，以下具体目标是。建议：目标#1：通过评估体外 TTP 的获得/损失，定义 TTP 作为 CTGF/CCN2 表达和并发 HSC 分化的负调节因子的作用。 #2：确定 TTP 抑制是否对酒精诱导的纤维化至关重要，并进一步研究 TTP 缺乏是否会恶化酒精诱导的纤维化。这项研究的结果将是对控制 TTP 表达的机制的基本、突破性的理解。酒精性肝纤维化中的促纤维化分子 CTGF/CCN2 这将对酒精性肝纤维化新疗法的开发产生重大影响。