Periostin Regulation of Lung Fibrosis

骨膜素对肺纤维化的调节

• 批准号: 8590983
• 负责人: Bethany B. Moore
• 金额: $ 39.57万
• 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/8590983
• 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; 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; receptor; 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

描述（由申请人提供）：肺纤维化的骨膜素调节特发性肺纤维化（IPF）是一种进行性肺部疤痕疾病，其特征是肌成纤维细胞的积累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，并且没有其他有效的治疗方法 比肺移植。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 TGFb 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点，因为 TGFb 或 TGFb 信号传导的完全丧失可能导致毁灭性的自身免疫炎症和死亡。因此，人们对鉴定 TGFb 信号转导的下游介质非常感兴趣，这可能是治疗纤维化疾病的更好的治疗干预目标。最近，TGFb 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进行研究的分子，已被认为与间质性纤维化肺病的发病机制有关。我们和其他人已经证明，IPF 患者的细胞和肺组织中的骨膜素增加，并且 IPF 患者循环骨膜素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-/-小鼠可以免受博来霉素诱导的纤维化的影响。我们最近证明骨膜素可以诱导间充质细胞增殖、胶原蛋白表达和闭合划伤伤口的能力。通过施用 OC-20 单克隆抗体阻断骨膜素与 avb3 和 avb5 整合素的相互作用，可以部分逆转骨膜素介导的伤口闭合，并在疾病的纤维增殖期施用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，骨膜素的结构来源和造血来源都是博莱霉素诱导的纤维化发展所必需的。初步数据表明，骨膜素可能通过诱导抗凋亡蛋白（生存素、X连锁凋亡抑制剂（XIAP）和Bcl-2）来诱导肌成纤维细胞存活。骨膜素在老年小鼠中也升高，可能导致老年小鼠对伽马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素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素在多种模型中调节纤维化发展中可能发挥的作用。 TGFb 和骨膜素相互调节；然而，骨膜蛋白缺陷小鼠仍能存活并且健康问题相对较少，这一事实表明该分子可能非常适合治疗靶向。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，并了解骨膜素如何影响肺间充质细胞的行为。最后，我们将测量 IPF 患者肺部的骨膜素以及循环骨膜素水平随时间的变化，并确定该生物标志物可能与疾病进展的相关性。我们假设基质细胞蛋白骨膜素促进肺纤维化的发生和进展，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设。目的 1) 确定骨膜素是否调节老年小鼠中异硫氰酸荧光素诱导的肺纤维化或伽马疱疹病毒诱导的纤维化的发展 目的 2) 确定动物模型中纤维细胞和纤维细胞源性骨膜素在肺纤维化发展中的作用 目的 3) 确定骨膜素和 TGFb 相互作用的分子机制 目的 4) 确定 IPF 患者血浆或支气管肺泡灌洗液中的骨膜素水平是否与疾病进展相关