Pathogenesis of NASH Cirrhosis

NASH 肝硬化的发病机制

• 批准号: 9131857
• 负责人: ANNA MAE ELIZABETH DIEHL
• 金额: $ 27.83万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9131857
• 关键词: Adherens Junction; Area; Automobile Driving; Back; Cell Nucleus; Cells; Cirrhosis; Coculture Techniques; Data; Disease; Duct (organ) structure; Early Diagnosis; Epidemic; Erinaceidae; Fibrosis; Gene Expression; Gene Targeting; Goals; Growth; Growth Factor; Health; Hepatic Stellate Cell; Human; Knockout Mice; Knowledge; Life; Ligands; Liver; Liver Fibrosis; Liver Regeneration; Mediating; Modeling; Molecular Target; Morbidity - disease rate; Mus; Myofibroblast; Natural regeneration; Nuclear; Pathogenesis; Pathway interactions; Patients; Peptide Signal Sequences; Peptides; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Prevention; Production; Proteins; Reaction; Recovery; Regulation; Research; Rodent; Severities; Signal Transduction; Work; base; feeding; fibrogenesis; human PTPRT protein; improved; inhibitor/antagonist; injured; insight; liver injury; mortality; new therapeutic target; nonalcoholic steatohepatitis; novel; novel diagnostics; novel therapeutic intervention; pleiotrophin; prevent; programs; receptor; repaired; smoothened signaling pathway; stellate cell; success; transcription factor

 DESCRIPTION (provided by applicant): Cirrhosis caused by nonalcoholic steatohepatitis (NASH) is common and life threatening. Gaps in knowledge about myofibroblasts, the fibrogenic cells that drive cirrhosis pathogenesis styme treatment of NASH-cirrhosis. In NASH-cirrhosis, myofibroblasts derive from resident stellate cells. We discovered that: 1) stellate cells must induce and maintain Hedgehog signaling to be myofibroblastic, 2) persistent Hedgehog activity causes progressive fibrosis, and 3) transient Hedgehog activation is necessary for liver regeneration. Hedgehog must be induced, and then suppressed, for recovery from NASH. Identifying the mechanisms which regulate Hedgehog signaling is imperative for defining novel therapeutic targets to reverse hepatic fibrosis. Herein, we evaluate a novel HYPOTHESIS that interaction of pleiotrophin (a myofibroblast-derived factor that promotes regeneration) and its receptor, protein tyrosine phosphatase receptor zeta-1 (PTPRZ1), prevents NASH- cirrhosis by antagonizing Hedgehog's pro-fibrogenic actions in myofibroblasts. Recently, we discovered that "degregulation" of pleiotrophin-Hedgehog signaling in PTPRZ1-expressing stellate cells might contribute to cirrhosis pathogenesis in NASH. Specifically, we found that livers with NASH are enriched with PTPRZ1(+) cells and showed that pleiotrophin antagonizes key actions of Hedgehog by studying pleiotrophin- and PTPRZ1-knockout mice. Studies in cultured stellate cells indicated that the mechanism is indirect and involves pleiotrophin-dependent inhibition of PTPRZ1's phosphatase activity, alteration of the phosphoproteome, and consequent changes in the cellular localization of Yes-activated peptide (YAP), a Hippo kinase-regulated transcriptional co-activator that controls liver growth. We propose a novel paradigm whereby myofibroblast fate is controlled by factors, such as Hedgehog and pleiotrophin, that modulate activation/inactivation of YAP. Our SPECIFIC AIMS are to: 1) determine how pleiotrophin inhibits Hedgehog activity in myofibroblasts and 2) determine how pleiotrophin-mediated inhibition of Hedgehog in myofibroblasts inhibits NASH cirrhosis. Successful completion of this proposal will identify new therapeutic targets for NASH cirrhosis and fill a gap in knowledge about the regulation of fibrotic liver injury.

 描述（由申请人提供）：非酒精性脂肪性肝炎（NASH）引起的肝硬化常见且危及生命。关于肌成纤维细胞的知识缺口，驱动肝硬化发病机制的纤维化细胞阻碍了NASH肝硬化的治疗。在NASH-肝硬化中，肌成纤维细胞来源于常驻星状细胞。我们发现：1）星状细胞必须诱导和维持Hedgehog信号传导以成为成肌纤维细胞，2）持续的Hedgehog活性导致进行性纤维化，以及3）短暂的Hedgehog激活是肝再生所必需的。Hedgehog必须被诱导，然后被抑制，以从NASH中恢复。确定调节Hedgehog信号传导的机制对于确定逆转肝纤维化的新治疗靶点至关重要。在此，我们评估了一种新的假说，即多效生长因子（一种促进再生的肌成纤维细胞衍生因子）及其受体蛋白酪氨酸磷酸酶受体ζ-1（PTPRZ 1）的相互作用，通过拮抗Hedgehog在肌成纤维细胞中的促纤维化作用来预防NASH-肝硬化。最近，我们发现PTPRZ 1表达的星状细胞中的多效生长因子-刺猬信号转导的“degregulation”可能有助于NASH中的肝硬化发病机制。具体来说，我们发现NASH的肝脏富含PTPRZ 1（+）细胞，并通过研究多效生长因子和PTPRZ 1基因敲除小鼠显示多效生长因子拮抗Hedgehog的关键作用。在培养的星状细胞中的研究表明，该机制是间接的，涉及PTPRZ 1的磷酸酶活性的多效生长因子依赖性抑制，磷酸化蛋白质组的改变，以及随后的Yes激活肽（雅普）细胞定位的变化，这是一种Hippo激酶调节的转录共激活因子，控制肝脏生长。我们提出了一种新的范式，即肌成纤维细胞的命运是由因素，如刺猬和多效营养因子，调节激活/失活的雅普。我们的具体目标是：1）确定多效生长因子如何抑制肌成纤维细胞中的Hedgehog活性和2）确定多效生长因子介导的抑制肌成纤维细胞中的Hedgehog如何抑制NASH肝硬化。该提案的成功完成将确定NASH肝硬化的新治疗靶点，并填补有关纤维化肝损伤调控的知识空白。