Control of Fibroblast Function by Prostaglandin E2 and Plasminogen Activation

前列腺素 E2 和纤溶酶原激活对成纤维细胞功能的控制

• 批准号: 8665457
• 负责人: MARC L PETERS-GOLDEN
• 金额: $ 39.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-11 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665457
• 关键词: Actins; Adhesions; Attention; Back; Binding Proteins; Biology; Breathing; Cessation of life; Cicatrix; Clinical; Collagen; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dinoprostone; Disease; Effector Cell; Eukaryotic Initiation Factor-4E; Event; Extracellular Matrix Proteins; F-Actin; Fibroblasts; Fibrosis; Focal Adhesion Kinase 1; Foundations; G-Protein-Coupled Receptors; Goals; Grant; Hamman-Rich syndrome; In Vitro; Knowledge; Laboratories; Ligation; Lung; Lung diseases; Mediating; Mediator of activation protein; Myofibroblast; Outcome; PTK2 gene; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Plasmin; Plasminogen; Prevention; Process; Production; Prostaglandins; Protein Biosynthesis; Protein Isoforms; Proteins; Pulmonary Fibrosis; Receptor Activation; Research; Resistance; Respiratory Failure; Ribosomal Protein S6; Ribosomal Protein S6 Kinase; Role; Scheme; Serum Response Factor; Signal Transduction; Signaling Protein; Testing; Therapeutic; Tissues; Transforming Growth Factors; Translations; Urokinase; Work; effective therapy; in vivo; insight; lipid mediator; mTOR protein; mouse model; myocardin; novel therapeutics; prevent; public health relevance; rho; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a devastating and usually fatal scarring disease. A pivotal effector cell in this disorder is the myofibroblast, with an exuberant capacity for elaboration of extracellular matrix proteins such as collagen that comprise tissue scars. Emerging research suggests that overactive adhesion/stiffness signaling and protein translation contribute to myofibroblast differentiation and activation. Less attention has been paid to endogenous anti- fibrotic pathways. Two such anti-fibrotic pathways that have been shown to be deficient in IPF are 1) the lipid mediator prostaglandin E2 (PGE2) and its associated G protein-coupled receptors and cyclic AMP (cAMP) effectors, and 2) the proteolytic cascade by which urokinase converts plasminogen to plasmin. We have previously shown that cross-talk between these two pathways is critical for their anti-fibrotic functions. Our new preliminary data suggest that PGE2, via cAMP and distinct isoforms of the classical cAMP effector protein kinase A, can inhibit both adhesion signaling and protein translation by targeting a variety of critical checkpoints. Moreover, our data suggest that, in addition to preventing myofibroblast differentiation, PGE2 can reverse the differentiated state of myofibroblasts back to fibroblasts; this has important therapeutic implications in view of the fact that most patients hav already advanced fibrosis on clinical presentation. The overall objectives of this proposal are to 1) understand the mechanisms by which PGE2 regulates adhesion signaling and protein translation; 2) determine whether plasmin has similar effects or if it instead potentiates the effects of PGE2; 3) determine the importance of disrupting adhesion signaling and protein translation in the ability of PGE2 to reverse myofibroblast differentiation; and 4) evaluate the potential of inhaled PGE2 and/or urokinase to ameliorate fibrosis and to reverse myofibroblast differentiation in vivo in two mouse models of pulmonary fibrosis. The proposed studies will provide new fundamental insights into fibroblast biology as well as translational control, and a potential new paradigm for therapeutics in IPF and other fibrotic lung diseases.

描述（由申请人提供）：特发性肺纤维化（IPF）是一种毁灭性且通常致命的疤痕疾病。在这种疾病中的关键效应细胞是肌成纤维细胞，具有旺盛的能力，用于制造细胞外基质蛋白，如胶原蛋白，包括组织疤痕。新兴的研究表明，过度活跃的粘附/僵硬信号和蛋白质翻译有助于肌成纤维细胞分化和活化。内源性抗纤维化途径的研究较少.已显示在IPF中缺乏的两种这样的抗纤维化途径是1）脂质介质前列腺素E2（PGE 2）及其相关的G蛋白偶联受体和环AMP（cAMP）效应物，和2）尿激酶将纤溶酶原转化为纤溶酶的蛋白水解级联。我们之前已经表明，这两种途径之间的串扰对其抗纤维化功能至关重要。我们新的初步数据表明，PGE 2通过cAMP和经典cAMP效应蛋白激酶A的不同亚型，可以通过靶向作用抑制粘附信号传导和蛋白质翻译。 各种关键检查点。此外，我们的数据表明，除了防止肌成纤维细胞分化外，PGE 2还可以将肌成纤维细胞的分化状态逆转回成纤维细胞;鉴于大多数患者在临床表现上已经具有晚期纤维化的事实，这具有重要的治疗意义。本提案的总体目标是：1）了解PGE 2调节粘附信号传导和蛋白质翻译的机制; 2）确定纤溶酶是否具有类似的作用，或者它是否反而增强PGE 2的作用; 3）确定破坏粘附信号传导和蛋白质翻译在PGE 2逆转肌成纤维细胞分化的能力中的重要性;和4）在两种肺纤维化小鼠模型中评估吸入的PGE 2和/或尿激酶改善纤维化和逆转体内肌成纤维细胞分化的潜力。拟议的研究将为成纤维细胞生物学以及翻译控制提供新的基本见解，并为IPF和其他纤维化肺病的治疗提供潜在的新范例。