Pathogenesis of NASH Cirrhosis

NASH 肝硬化的发病机制

基本信息

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
项目类别：
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

项目摘要

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) 引起的肝硬化很常见，并且危及生命。对于肌成纤维细胞（驱动肝硬化发病机制的纤维形成细胞）的了解存在空白。 NASH 肝硬化中，肌成纤维细胞源自居民。我们发现：1）星状细胞必须诱导和维持。 Hedgehog 信号是肌成纤维细胞，2) 持续的 Hedgehog 活性会导致进行性纤维化，3) 短暂的 Hedgehog 激活对于肝脏再生是必要的，为了从 NASH 中恢复，必须诱导并抑制 Hedgehog 信号传导。为了确定逆转肝纤维化的新治疗靶标，我们评估了多效蛋白（a）相互作用的新假设。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 zeta-1 (PTPRZ1) 通过拮抗 Hedgehog 在表达 PTPRZ1 的星状细胞中的促纤维化作用来预防 NASH 肝硬化。具体来说，我们发现 NASH 的肝脏富含 PTPRZ1(+) 细胞，并通过研究多效蛋白和 PTPRZ1 敲除小鼠的研究表明多效蛋白拮抗 Hedgehog 的关键作用，该机制是间接的。并涉及多效蛋白依赖性 PTPRZ1 磷酸酶活性的抑制，改变我们提出了一种新的范例，其中肌成纤维细胞的命运由 Hedgehog 和多效蛋白等因子控制。，调节 YAP 的激活/失活，我们的具体目标是：1) 确定多效蛋白如何抑制 Hedgehog 活性。 2）确定肌成纤维细胞中多效蛋白介导的 Hedgehog 抑制如何抑制 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节的知识空白。