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（由应用提供）：肝纤维化（LF）/肝硬化是全球主要的健康问题，也是世界上发病和死亡率的主要原因之一。酗酒是发达国家肝纤维化/肝硬化最常见的原因之一，占肝硬化病例的50％以上。目前，没有有效的LF治疗方法。酒精性肝纤维发生从细胞因子和肝星状细胞（HSC）激活和转分化为肌纤维蛋白之间的失衡而发展。减轻这些纤维化机制是迈向开发LF的新治疗干预措施的重要一步。我们的长期目标是阐明LF病理学中的调节机制，这是将最小化或逆转纤维化的治疗剂开发的必要先决条件。 CTGF/CCN2（结缔组织生长因子，CTGF）是一种稳定的纤维化蛋白，可促进HSC粘合剂，增殖，运动和胶原蛋白产生。在纤维化肝脏中，CTGF/CCN2由HSC，成纤维细胞，肌纤维细胞，内皮细胞和胆管上皮细胞产生。 CTGF/CCN2表达促进LF。 CTGF给药可显着上调I型胶原蛋白合成，并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。通过纤维化炎症介质TGF-β刺激后，培养的HSC中的CTGF/CCN2表达得到了增强。成纤维细胞中CTGF/CCN2的丧失会改善胶原蛋白沉积和对化学诱导的皮肤纤维化的抗性。 CTGF/CCN2的敲除可以防止LF，因此其活性/表达的调节代表了该疾病中的一种新型治疗靶标。然而，调节CTGF​​/CCN2 mRNA表达和肝纤维化延长稳定性的因素尚不清楚。 Tristetraprolin（TTP）是一种不稳定mRNA的mRNA结合蛋白，导致蛋白质表达降低。但是，TTP表达与CTGF的稳定性之间的联系尚不清楚。与其他时间相比，TTP仅在肝脏中高度表达。此外，在乙型肝炎病毒（HBV）相关的肝硬化中证明了TTP的显着下调。但是，尚未探索TTP在控制纤维化CTGF/CCN2表达中的作用。我们已经开发了一个新的假设，即TTP充当CGF/CCN2表达的mRNA衰减器，而TTP的丧失导致肝星状晶状体细胞（HSC）激活（HSC）激活和转分化成肌纤维纤维细胞。为了检验这一假设，提出了以下特定目的：目标＃1：通过评估体外评估TTP的增益/损失，将TTP视为负CTGF/CCN2表达和同一HSC分化的作用。目标＃2：确定TTP抑制对于酒精诱导的纤维化至关重要，并进一步检查TTP缺乏是否加剧了酒精诱导的纤维化。这项研究的结果将是对控制酒精LF中纤维化分子CTGF/CCN2表达的机制的基本，开创性的理解。这将对酒精性肝纤维化的新疗法的发展产生重大影响。