Periostin Regulation of Lung Fibrosis

骨膜素对肺纤维化的调节

• 批准号: 8704825
• 负责人: Bethany B. Moore
• 金额: $ 40.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704825
• 关键词: Adoptive Transfer; Animal Model; Apoptosis; Apoptotic; Asthma; Atherosclerosis; Autoimmune Process; BCL2 gene; Behavior; Biological Markers; Bleomycin; Blood; Bone Marrow; Breeding; Bronchoalveolar Lavage Fluid; Cell Proliferation; Cells; Chimera organism; Cicatrix; Collagen; Data; Deposition; Development; Diphtheria Toxin; Disease; Disease Progression; Extracellular Matrix; Fibroblasts; Fibrosis; Fluorescein; Future; Gases; Growth Factor Receptors; Hamman-Rich syndrome; Health; Hematopoietic; Impairment; Inflammation; Integrins; Isothiocyanates; Lead; Lung; Lung Transplantation; Lung diseases; Malignant Neoplasms; Measurement; Measures; Mediating; Mediator of activation protein; Mesenchymal; Modeling; Molecular; Mus; Myofibroblast; Organ Model; Pathogenesis; Patients; Phase; Plasma; Play; Predisposition; Proteins; Publishing; Pulmonary Fibrosis; Regulation; Resistance; Respiratory Failure; Respiratory physiology; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Source; Structure of parenchyma of lung; Tamoxifen; Terminator Codon; Testing; Therapeutic Intervention; Time; Transforming Growth Factors; aged; base; cell behavior; diphtheria toxin receptor; effective therapy; gammaherpesvirus; human BIRC4 protein; in vivo; in vivo Model; interest; interstitial; lung development; monocyte; mortality; novel; overexpression; paracrine; periostin; promoter; recombinase; research study; survivin; therapeutic target; wound

DESCRIPTION (provided by applicant): Periostin Regulation of Lung Fibrosis Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disorder of the lung that is characterized by the accumulation of myofibroblasts and the deposition of extracellular matrix leading to respiratory failure. Unfortunately, the disease is fatal and there are no effective therapies other than lung transplantation. The most potent profibrotic mediator studied to date is transforming growth factor (TGF) b and TGFb is elevated in many models of organ fibrosis. Unfortunately, TGFb is a difficult therapeutic target as total loss of TGFb or TGFb signaling can cause devastating autoimmune inflammation and mortality. As such, there is great interest in identifying downstream mediators of TGFb signaling which may be better targets for therapeutic intervention to treat fibrotic disorders. Recently, the TGFb-regulated matricellular protein, periostin, a molecule which has been studied in asthma, atherosclerosis and cancer, has been implicated in the pathogenesis of interstitial fibrotic lung disease. We and others have shown that periostin is increased in cells and lung tissue of IPF patients and that elevated levels of circulating periostin in IPF patients predict declines in lung function. Additionally, we and other have demonstrated that periostin-/- mice are protected from bleomycin-induced fibrosis. We recently demonstrated that periostin can induce mesenchymal cell proliferation, collagen expression and ability to close a scratch wound. Blockade of periostin interactions with the avb3 and avb5 integrins via the administration of the OC-20 monoclonal Ab could partially reverse periostin-mediated wound closure and partially blocks the development of bleomycin-induced fibrosis when administered during the fibroproliferative phase of the disease. Our published results using bone marrow chimeric mice indicate that both structural and hematopoietic sources of periostin are required for development of bleomycin-induced fibrosis. Preliminary data show that periostin may induce myofibroblast survival via the induction of the anti- apoptotic proteins (survivin, X-linked inhibitor of apoptosis (XIAP) and Bcl-2). Periostin is also elevated in aged mice and may contribute to the enhanced susceptibility of aged mice to gammaherpesvirus-induced fibrosis. Our revised studies are aimed at verifying the ability of periostin to promote fibrosis in two additional animal models. We also have proposed studies to elucidate the role that circulating fibrocytes and fibrocyte-derived periostin may play in regulating fibrotic development in multiple models. TGFb and periostin reciprocally regulate each other; however, the fact that periostin-deficient mice are viable and have relatively few health issues suggests that this molecule may be highly amenable to therapeutic targeting. To further explore this possibility, we will perform mechanistic studies to understand the reciprocal regulation of these mediators and to understand how periostin influences lung mesenchymal cell behavior. Finally, we will measure periostin in the lung and the changes in circulating periostin levels over time in IPF patients and determine the correlations this biomarker may have on disease progression. We hypothesize that the matricellular protein, periostin, promotes the development and progression of pulmonary fibrosis and may serve as a biomarker for disease progression. We will mechanistically explore this hypothesis in the following specific aims. Aim 1) To determine whether periostin regulates the development of fluorescein isothiocyanate-induced pulmonary fibrosis or gammaherpesvirus-induced fibrosis in aged mice Aim 2) To determine the contribution of fibrocytes and fibrocyte-derived periostin in the development of lung fibrosis in animal models Aim 3) To determine the molecular mechanisms via which periostin and TGFb regulate each other and the function of lung mesenchymal cells Aim 4) To determine whether periostin levels in plasma or bronchoalveolar lavage fluid of IPF patients correlate with disease progression

特发性肺纤维化（IPF）是一种进行性肺瘢痕形成疾病，其特征在于肌成纤维细胞的积聚和细胞外基质的沉积，导致呼吸衰竭。不幸的是，这种疾病是致命的，没有有效的治疗方法， 比肺移植更重要迄今为止研究的最有效的促纤维化介质是转化生长因子（TGF）B，并且TGF B在许多器官纤维化模型中升高。不幸的是，TGFb是一个困难的治疗靶标，因为TGFb或TGFb信号传导的完全丧失可导致破坏性的自身免疫性炎症和死亡。因此，对鉴定TGF β信号传导的下游介质存在极大的兴趣，所述下游介质可以是治疗纤维化病症的治疗性干预的更好靶点。最近，TGF β调节的基质细胞蛋白，骨膜蛋白，一种在哮喘，动脉粥样硬化和癌症中研究的分子，已经被牵连到间质纤维化肺病的发病机制中。我们和其他人已经表明，在IPF患者的细胞和肺组织中，骨膜蛋白增加，并且IPF患者中循环骨膜蛋白水平升高预测肺功能下降。此外，我们和其他人已经证明，骨膜蛋白-/-小鼠免受博莱霉素诱导的纤维化。我们最近证明，骨膜蛋白可以诱导间充质细胞增殖，胶原蛋白表达和关闭划痕伤口的能力。通过给予OC-20单克隆抗体阻断骨膜蛋白与avb 3和avb 5整联蛋白的相互作用，可部分逆转骨膜蛋白介导的伤口闭合，并在疾病的纤维增生期给予时部分阻断博来霉素诱导的纤维化的发展。我们发表的使用骨髓嵌合小鼠的结果表明，骨膜蛋白的结构和造血来源都是博来霉素诱导的纤维化发展所必需的。初步数据显示，骨膜蛋白可通过诱导抗凋亡蛋白（存活素、X连锁凋亡抑制剂（XIAP）和Bcl-2）诱导肌成纤维细胞存活。骨膜蛋白在老年小鼠中也升高，可能有助于老年小鼠对γ疱疹病毒诱导的纤维化的易感性增强。我们修订的研究旨在验证骨膜蛋白在另外两种动物模型中促进纤维化的能力。我们还提出了研究来阐明循环纤维细胞和纤维细胞衍生的骨膜蛋白在多种模型中调节纤维化发展中可能发挥的作用。TGF β和骨膜蛋白相互调节;然而，骨膜蛋白缺陷小鼠是可行的并且具有相对较少的健康问题的事实表明，这种分子可能非常适合于治疗靶向。为了进一步探索这种可能性，我们将进行机制研究，以了解这些介质的相互调节，并了解骨膜蛋白如何影响肺间充质细胞的行为。最后，我们将测量IPF患者肺中的骨膜蛋白和循环骨膜蛋白水平随时间的变化，并确定该生物标志物可能与疾病进展的相关性。我们推测，基质细胞蛋白，骨膜蛋白，促进肺纤维化的发展和进展，并可能作为疾病进展的生物标志物。我们将在下面的具体目标中机械地探讨这个假设。目的1）确定periostin是否调节异硫氰酸荧光素诱导的老年小鼠肺纤维化或γ-疱疹病毒诱导的肺纤维化的发展。目的2）确定纤维细胞和纤维细胞衍生的periostin在动物模型肺纤维化发展中的作用。目的3）确定periostin和TGF β相互调节的分子机制以及肺间充质细胞的功能。目的4）确定IPF患者血浆或支气管肺泡灌洗液中的骨膜蛋白水平是否与疾病进展相关