Therapeutic Strategies for Environmental Lung Diseases

环境性肺病的治疗策略

基本信息

批准号：
7295871
负责人：
James Christopher Bonner
金额：
$ 22.28万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7295871
关键词：
Address Affect Allergens Anti-Inflammatory Agents Anti-inflammatory Asthma Binding Bioavailable Bleomycin Blood Circulation Breathing Cell Surface Receptors Cell surface Cells Chemotaxis Child Chronic Chronic lung disease Cicatrix Clinical Treatment Clinical Trials Collagen Complication Connective Tissue Cells Data Deposition Development Diabetes Mellitus Diagnosis Disease Dose Environmental Exposure Exposure to Fibroblasts Fibrosis Figs - dietary Future Genetic Predisposition to Disease Gleevec Glucocorticoids Growth Growth Factor Health Human Imatinib Imatinib mesylate In Vitro Inflammatory Interleukin-13 Ligands Lung Lung diseases Mediating Mediator of activation protein Membrane Modeling Molecular Mus Myofibroblast Nature Oral Administration Outcome Ovalbumin PDGF receptor tyrosine kinase PDGFRB gene Pathogenesis Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Phosphorylation Platelet Inhibitors Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Play Prevention Process Production Protein Isoforms Protein Tyrosine Kinase Pulmonary Fibrosis Receptor Protein-Tyrosine Kinases Research Respiratory physiology Risk Role STAT6 Transcription Factor Signal Transduction Source System Testing Therapeutic Tissues Transition Elements Treatment Protocols Tyrosine Kinase Inhibitor United States Vanadium Work autocrine bis(maltolato)oxovanadium(IV)cell type concept cytokine design diabetes mellitus therapy fibrogenesis improved in vivo indium-bleomycin inhibitor/antagonist innovation interstitial intraperitoneal lung injury migration mouse model neutralizing antibody neutralizing monoclonal antibodies oxovanadium IV pre-clinical receptor receptor binding research study response response to injury small molecule toxicant transcription factor translational approach

项目摘要

DESCRIPTION (provided by applicant): There are currently no effective strategies for the treatment of chronic airway fibrosis in asthma or interstitial pulmonary fibrosis that result from environmental exposures to a wide variety of inhaled allergens and toxicants. It is generally accepted that current anti-inflammatory therapies fail to improve fibrotic outcomes in the lung. Therefore, the development of translational approaches that target fibrosis are urgently needed. Our work has shown that interleukin (IL)-13, a key mediator of asthma and fibrosis, stimulates the production of platelet-derived growth factor (PDGF). The binding of PDGF to cell-surface PDGF receptors results in the proliferation of fibroblasts, the principal cell type that secretes collagen to form fibrotic scar tissue. IL-13-induced PDGF production by lung cells is tightly regulated by STAT transcription factors; STAT-6 promotes IL-13-induced PDGF production while STAT-1 suppresses PDGF production. The primary objective of this project is to explore innovative strategies aimed at reducing IL-13-induced PDGF signaling and fibrosis. Our hypothesis is that inhibition of PDGF production, PDGF receptor binding, or PDGF receptor phosphorylation will reduce airway or interstitial fibrosis in established mouse models of chronic lung disease. In the first aim we will determine whether the oral administration of bis(maltolato)oxovanadium(IV) (BMOV), a bioavailable form of vanadium that is used for diabetes therapy, decreases PDGF levels and airway fibrosis in vivo in mouse models of asthma and interstitial pulmonary fibrosis. Because vanadium activates STAT-1 to reduce IL-13-induced PDGF production in lung cells in vitro, we will determine if BMOV reduces airway fibrosis in vivo using the ovalbumin mouse model of asthma and in a bleomycin mouse model of interstitial fibrosis. In the second aim we will determine whether administration of a monoclonal neutralizing antibody to selectively block PDGF binding to the PDGF receptor reduces fibrosis in mouse models of asthma and pulmonary fibrosis. In the final aim, we will determine whether blocking PDGF receptor tyrosine kinase activity reduces fibrosis in a mouse model of asthma. This aim will utilize the receptor tyrosine kinase inhibitor, imatinib mesylate, to block PDGFR phosphorylation. If any one of the three proposed strategies for blocking PDGF signaling result in amelioration of fibrosis, then this would provide a breakthrough for future application to clinical trials aimed at the treatment of airway fibrosis in asthma or interstitial pulmonary fibrosis. Asthma and pulmonary fibrosis are chronic lung diseases that result from environmental exposure and genetic susceptibility to a wide variety of inhaled allergens and toxicants. In the United States there are over 200,000 patients with pulmonary fibrosis, and of these over 40,000 expire annually. 20 million people in the United States have been diagnosed with asthma and nearly 9 million of them are children. Therefore, these chronic lung diseases clearly pose a major health problem. Airway fibrosis in asthma is part of a chronic remodeling process that contributes to the obstructive nature of this disease and reduces lung function. Moreover, there are currently no effective treatment strategies to reduce airway fibrosis in chronic asthma, nor are drugs available that significantly reduce interstitial pulmonary fibrosis. We will attempt to develop preclinical strategies aimed at reducing growth factor signaling, fibroblast proliferation, and collagen deposition in mouse models of chronic asthma and interstitial pulmonary fibrosis.

描述（由申请人提供）：目前尚无有效的策略来治疗哮喘或间质性肺纤维化中的慢性气道纤维化，这是由于环境暴露于各种吸入过敏原和毒物的环境暴露而导致的。人们普遍认为，当前的抗炎疗法无法改善肺部的纤维化预后。因此，迫切需要采用靶向纤维化的翻译方法的发展。我们的工作表明，白介素（IL）-13是哮喘和纤维化的关键介体，刺激了血小板衍生的生长因子（PDGF）的产生。 PDGF与细胞表面PDGF受体的结合导致成纤维细胞的增殖，成纤维细胞类型是分泌胶原蛋白形成纤维化疤痕组织的主要细胞类型。 IL-13诱导的肺细胞产生的PDGF受到STAT转录因子的严格调节。 Stat-6促进IL-13诱导的PDGF产生，而STAT-1抑制PDGF的产生。该项目的主要目的是探索旨在减少IL-13诱导的PDGF信号传导和纤维化的创新策略。我们的假设是，在已建立的慢性肺部病小鼠模型中，抑制PDGF产生，PDGF受体结合或PDGF受体磷酸化将减少气道或间质纤维化。在第一个目的中，我们将确定BIS（Maltolato）Oxovanadium（IV）（BMOV）的口服给药，这是一种用于糖尿病治疗的可生物利用形式，可降低PDGF水平和体内气道纤维化的哮喘和内膜肺纤维纤维纤维纤维的体内。由于钒在体外激活STAT-1以减少IL-13诱导的肺细胞中PDGF产生，因此我们将使用哮喘的卵脂蛋白小鼠模型和中质纤维化的Bleymycin小鼠模型来确定BMOV是否会降低体内气道纤维化。在第二个目的中，我们将确定单克隆中和抗体的给药是否可以选择性地阻断PDGF与PDGF受体结合，从而减少哮喘和肺纤维化小鼠模型中的纤维化。在最终目标中，我们将确定阻断PDGF受体酪氨酸激酶活性是否会减少哮喘小鼠模型中的纤维化。该目的将利用受体酪氨酸激酶抑制剂伊马替尼梅赛酸盐来阻断PDGFR磷酸化。如果三种阻止PDGF信号传导的策略中的任何一种会导致纤维化的改善，那么这将为将来应用于旨在治疗哮喘或间质肺纤维化治疗气道纤维化的临床试验的突破。哮喘和肺纤维化是由于环境暴露和对多种吸入过敏原和毒物的遗传敏感性引起的慢性肺疾病。在美国，有超过200,000例肺纤维化患者，其中40,000多人每年到期。美国有2000万人被诊断出患有哮喘，其中近900万是儿童。因此，这些慢性肺部疾病显然是一个重大的健康问题。哮喘中气道纤维化是慢性重塑过程的一部分，该过程有助于该疾病的阻塞性质并降低肺功能。此外，目前尚无有效的治疗策略来减少慢性哮喘中气道纤维化，也没有大幅度降低间质肺纤维化的药物。我们将尝试制定旨在减少生长因子信号传导，成纤维细胞增殖和胶原蛋白沉积的临床前策略。