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）：骨膜素对特发性肺纤维化（IPF）的调节是一种肺的进行性疤痕疾病，其特征在于肌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，没有其他有效的疗法 比肺移植。迄今为止，最有效的纤维化介质是在许多器官纤维化模型中转化生长因子（TGF）B和TGFB升高。不幸的是，TGFB是一个困难的治疗靶标，因为TGFB或TGFB信号传导的总损失可能导致毁灭性的自身免疫性炎症和死亡率。因此，人们非常有兴趣识别TGFB信号的下游介质，这可能是治疗纤维性疾病的治疗干预措施的更好靶标。最近，由TGFB调节的母细胞蛋白骨膜素是一种已在哮喘，动脉粥样硬化和癌症研究的分子，与间质纤维化肺部疾病的发病机理有关。我们和其他人已经表明，IPF患者的细胞和肺组织骨膜素的增加，IPF患者循环蛋白的循环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 - / - 小鼠受到博来霉素诱导的纤维化的保护。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刮擦伤的能力。通过OC-20单克隆AB的给药来阻断与AVB3和AVB5整合素的相互作用，可以部分逆转骨膜蛋白介导的伤口闭合，并部分阻断疾病的纤维增生相期间给予博霉素诱导的纤维化的发展。我们使用骨髓嵌合小鼠发表的结果表明，骨膜素的结构和造血来源都是博来霉素诱导的纤维化所必需的。初步数据表明，骨膜素可能通过诱导抗凋亡蛋白（Survivin，X连接的凋亡抑制剂（XIAP）和BCL-2）诱导肌纤维细胞存活。骨膜素在老年小鼠中也升高，可能有助于增强老年小鼠对γ掌病毒诱导的纤维化的敏感性。我们的修订研究旨在验证骨膜素在另外两个动物模型中促进纤维化的能力。我们还提出了研究，以阐明循环纤维细胞和纤维细胞衍生的骨化蛋白可能在调节多种模型中纤维化发育方面发挥作用的作用。 TGFB和骨膜素相互调节；但是，骨膜缺乏小鼠的可行性，并且健康问题相对较少，这一事实表明该分子可能高度适合治疗靶向。为了进一步探索这种可能性，我们将进行机械研究，以了解这些介体的相互调节，并了解骨膜素如何影响肺间充质细胞行为。最后，我们将在IPF患者中测量肺中的骨膜蛋白以及随着时间的流逝循环骨膜素水平的变化，并确定该生物标志物在疾病进展方面的相关性。我们假设母细胞蛋白骨膜蛋白促进了肺纤维化的发育和发展，并且可以作为疾病进展的生物标志物。我们将在以下特定目标中机械学探讨这一假设。目的1）确定骨膜蛋白调节异硫氰酸荧光素诱导的肺纤维化或γ-手掌病毒诱导的衰老小鼠的纤维化的目的2）相互调节，肺间充质细胞的功能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