Role for tissue-type plasminogen activator in suppression of hepatic fibrosis

组织型纤溶酶原激活剂在抑制肝纤维化中的作用

• 批准号: 8460858
• 负责人: Liang-I Kang
• 金额: $ 4.72万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-06 至 2014-06-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460858
• 关键词: Active Sites; Acute; Address; Affinity; Alcoholism; Alteplase; Architecture; Archives; Cell Culture Techniques; Cell Differentiation process; Cell Maturation; Cells; Chronic; Chronic Hepatitis; Chronic Hepatitis C; Cicatrix; Cirrhosis; Clinical; Development; Disease; Drug or chemical Tissue Distribution; Etiology; Extracellular Matrix; Extracellular Matrix Proteins; FDA approved; Fibroblasts; Fibrosis; Healthcare; Hepatic Stellate Cell; Hereditary Disease; Human; In Situ Hybridization; In Vitro; Inflammatory; Kidney; Knockout Mice; LDL-Receptor Related Protein 1; Laboratories; Lipoprotein Receptor; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver Regeneration; Liver diseases; Mediating; Mediator of activation protein; Messenger RNA; Methods; Molecular; Mutation; Myofibroblast; Normal tissue morphology; Outcome; Patients; Peptide Hydrolases; Phenotype; Phosphorylation; Plasminogen Activator; Play; Prevalence; Prevention; Process; Proteins; Rattus; Receptor Signaling; Rodent Model; Role; Signal Transduction; Techniques; Testing; Tissues; cell behavior; cost; extracellular; in vivo; inhibitor/antagonist; injured; liver function; liver injury; loss of function; neutralizing antibody; non-alcoholic fatty liver; novel strategies; receptor; receptor-mediated signaling; therapeutic target; therapy development; transdifferentiation

DESCRIPTION (provided by applicant): Liver fibrosis (scarring) develops as a consequence of a variety of chronic inflammatory liver diseases, and if untreated, will progress into cirrhosis and liver failure. With the dramatic increased prevalence of non-alcoholic fatty liver disease and chronic hepatitis C worldwide, it is expected that the health care impact and cost of liver cirrhosis will dramatically increase in the next 10-20 years. Unfortunately, no therapy currently available directly regulates the process of liver fibrosis. Hepatic stellate cells (HSCs) have been regarded as a central cellular mediator of fibrosis during chronic liver injury. Upon activation, they transform into myofibroblast-like cells that promote the accumulation of extracellular matrix proteins, eventually distorting liver architecture and impairing liver function. Recent studies on a known extracellular matrix-regulating protease, tissue-type plasminogen activator (t-PA), have shown that it can play a role in modulating tissue fibrosis development [1-3]. Preliminary studies presented in this proposal indicate that exogenous administration of active t-PA can antagonize and reverse the pro-fibrotic phenotype of hepatic stellate cells in vitro. Therefore, this proposal is directed at testing the hypothesis that t-PA normally suppresses the myofibroblast-like cell differentiation of HSCs following acute hepatic injury and that the loss of this function results in fibrosis/cirrhosis. The aims of this study are: 1) to investigate the potential proteolytic functions of t-PA in suppressing liver fibrosis 2) to determine the potential signaling functions of t-PA in suppressing liver fibrosis, and 3) to determine the changes that occur in tissue distribution of the PAs and their interacting partners between normal and chronically injured liver. Should the stated hypothesis prove correct, targeted administration of t-PA may be a novel strategy for the treatment and/or prevention of liver cirrhosis resulting from a variety of etiologies (e.g. NALFD, chronic hepatitis, genetic disorders, and alcoholism). Since t-PA is already FDA-approved for clinical use, the impact of this project is tremendous in terms of potential expedited development of therapies for liver cirrhosis patients who currently have limited treatment options.

描述（由申请人提供）：肝纤维化（疤痕）是多种慢性炎症性肝病的结果，如果不治疗，将发展为肝硬化和肝衰竭。随着全球非酒精性脂肪肝和慢性丙型肝炎患病率的急剧上升，预计未来 10-20 年肝硬化的医疗保健影响和费用将急剧增加。不幸的是，目前没有可用的疗法可以直接调节肝纤维化的过程。肝星状细胞（HSC）被认为是慢性肝损伤期间纤维化的中心细胞介质。激活后，它们转化为肌成纤维细胞样细胞，促进细胞外基质蛋白的积累，最终扭曲肝脏结构并损害肝功能。最近对已知的细胞外基质调节蛋白酶组织型纤溶酶原激活剂 (t-PA) 的研究表明，它可以在调节组织纤维化发展中发挥作用 [1-3]。该提案中提出的初步研究表明，外源性给予活性t-PA可以在体外拮抗和逆转肝星状细胞的促纤维化表型。因此，本提案旨在检验以下假设：t-PA 通常会抑制急性肝损伤后 HSC 的肌成纤维细胞样细胞分化，并且该功能的丧失会导致纤维化/肝硬化。本研究的目的是：1) 研究 t-PA 在抑制肝纤维化中的潜在蛋白水解功能；2) 确定 t-PA 在抑制肝纤维化中的潜在信号传导功能；3) 确定正常肝脏和慢性损伤肝脏之间 PA 及其相互作用伙伴的组织分布发生的变化。如果上述假设被证明是正确的，t-PA 的靶向给药可能是治疗和/或预防由多种病因（例如 NALFD、慢性肝炎、遗传性疾病和酗酒）引起的肝硬化的新策略。由于 t-PA 已获得 FDA 批准用于临床，因此该项目的影响是巨大的，有可能加快目前治疗选择有限的肝硬化患者的治疗方法的开发。