Periostin Regulation of Lung Fibrosis

描述(申请人提供)：Periostin对肺纤维化的调节特发性肺纤维化(IPF)是一种进行性的肺部疤痕疾病，其特征是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，没有其他有效的治疗方法。 而不是肺移植。到目前为止，研究中最有效的促纤维化介质是转化生长因子b，在许多器官纤维化模型中，转化生长因子b升高。不幸的是，TGFb是一个很难治疗的靶点，因为TGFb或TGFb信号的完全缺失可以导致毁灭性的自身免疫性炎症和死亡。因此，人们对确定TGFb信号的下游介质有很大兴趣，这些介质可能是治疗纤维化疾病的更好的干预靶点。近年来，TGFb调节的基质细胞蛋白Periostin已被研究在哮喘、动脉粥样硬化和癌症中，并与间质性纤维性肺疾病的发病机制有关。我们和其他人已经证明了IPF患者细胞和肺组织中Periostin的增加，IPF患者循环中Periostin水平的升高预示着肺功能的下降。此外，我们和其他人已经证明，Periostin-/-小鼠可以免受博莱霉素诱导的纤维化的保护。我们最近证实，Periostin可以诱导间充质细胞增殖、胶原表达和愈合划痕伤口的能力。通过OC-20单抗阻断Periostin与avb3和avb5整合素的相互作用，可以部分逆转Periostin介导的伤口闭合，并部分阻止在疾病的纤维增生期应用博莱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，博莱霉素诱导的纤维化的发展需要Periostin的结构和造血源。初步研究表明，Periostin可能通过诱导抗凋亡蛋白(Survivin、X连锁凋亡抑制因子(XIAP)和Bcl2)诱导肌成纤维细胞存活。Periostin在老年小鼠中也升高，可能有助于提高老年小鼠对伽马疱疹病毒诱导的纤维化的易感性。我们的修订研究旨在验证Periostin在另外两个动物模型中促进纤维化的能力。我们还提出了一些研究，以阐明循环中的纤维细胞和纤维细胞衍生的Periostin可能在多种模型中调节纤维化发展中的作用。TGFb和Periostin相互调节；然而，Periostin缺陷小鼠存活和相对较少的健康问题这一事实表明，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Periostin如何影响肺间充质细胞的行为。最后，我们将测量IPF患者肺组织中的Periostin和循环Periostin水平随时间的变化，并确定该生物标记物可能与疾病进展的相关性。我们假设基质细胞蛋白Periostin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。我们将在以下具体目标中机械地探索这一假说。目的：1)探讨Periostin对异硫氰酸荧光素诱导的老年小鼠肺纤维化或伽马疱疹病毒诱导的肺纤维化的作用。目的2)探讨纤维细胞和纤维细胞衍生的Periostin在肺纤维化动物模型中的作用。目的3)探讨Periostin和TGFb相互调节的分子机制及肺间充质细胞的功能。目的4)探讨IPF患者血浆或支气管肺泡灌洗液中Periostin水平与疾病进展的关系

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