The Role of the STAT Pathway in Airway Remodeling

STAT 通路在气道重塑中的作用

• 批准号: 6548281
• 负责人: AMY Rebecca SIMON
• 金额: $ 38.89万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-10 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6548281
• 关键词: JAK kinase; asthma; biological signal transduction; bronchus; cell cycle; cell proliferation; cytokine receptors; disease /disorder model; fibrosis; gene targeting; genetically modified animals; inflammation; interleukin 11; laboratory mouse; mitogen activated protein kinase; mitogens; myogenesis; phosphatidylinositol 3 kinase; platelet derived growth factor; protein kinase; respiratory epithelium; respiratory muscles; smooth muscle; tissue /cell culture; transcription factor

Asthma prevalence and mortality have increased steadily over the last decade. These facts highlight the need for a better understanding of the cellular and molecular mechanisms that contribute to the pathogenesis of asthma. While the pathophysiologic manifestations of this disease have traditionally been thought to be reversible, there is now evidence that in some asthmatics structural changes to the airway occur that can lead to persistent obstruction and bronchial hyperactivity. These structural changes, referred to as airway remodeling, include an increase in airway smooth muscle mass, mucous gland hyperplasia, and disruption of airway epithelium and subepithelial fibrosis. Furthermore, published data support that increased smooth muscle mass is likely the major determinant of airflow limitation in asthmatics with chronic obstruction. As a result, it is critical to understand the molecular mechanisms of airway smooth muscle growth that underlie these chronic changes in asthmatic airways. Both in vitro and in vivo studies suggest that the growth factor PDGF and the cytokine IL-11 are important contributors to airway smooth muscle cell proliferation. These mitogens signal via unique receptors that either have inherent tyrosine kinase activity or that lead to activation of the mitogen-activated protein kinase and phosphoinositol-3-kinase pathways. We and others have shown that these proximal pathways also converge to activate the Janus kinases (Jak) and signal transducers and activators of transcription (STAT; Jak-STAT pathway). This proposal seeks to test the hypothesis, using both in vitro and in vivo models, that activation of the Jak-STAT pathway plays a central role in airway smooth muscle mitogenesis and airway remodeling. Our specific aims are to: 1) To characterize PDGF- and IL-11-mediated activation of the Jak-STAT pathway in HASMC, 2) To determine the mechanisms of STAT-induced proliferation in HASMC and 3) To examine the role of the Jak-STAT pathway in ASM proliferation in two different animal models of airway remodeling. It is anticipated that these studies will contribute to our understanding of the mechanisms of chronic airway inflammation and subsequent remodeling seen in asthma, and may provide novel therapeutic strategies for this common and debilitating pulmonary disorder.

在过去的十年中，哮喘患病率和死亡率稳步增长。 这些事实强调了需要更好地理解有助于哮喘发病机理的细胞和分子机制。 尽管传统上认为这种疾病的病理生理表现是可逆的，但现在有证据表明，在某些哮喘患者中，气道的结构变化可能导致持续的阻塞和支气管中的过度活动。 这些结构性变化（称为气道重塑）包括气道平滑肌质量增加，粘液腺增生以及气道上皮和上皮下纤维化的破坏。 此外，发表的数据支持，增加平滑肌质量可能是慢性阻塞哮喘患者气流限制的主要决定因素。 结果，了解气道平滑肌生长的分子机制至关重要，这是哮喘气道这些慢性变化的基础。 体外和体内研究都表明，生长因子PDGF和细胞因子IL-11是气道平滑肌细胞增殖的重要因素。 这些有丝分裂原子通过具有固有酪氨酸激酶活性的独特受体信号，或者导致有丝分裂原激活的蛋白激酶和磷酸肌醇-3-激酶途径的激活。 我们和其他人表明，这些近端途径也会收敛以激活Janus激酶（JAK）和信号传感器和转录的激活因子（STAT; JAK-STAT途径）。 该提案旨在使用体外和体内模型来检验该假设，即JAK-Stat途径的激活在气道平滑肌有丝分裂和气道重塑中起着核心作用。 我们的具体目的是：1）表征HASMC中JAK-STAT途径的PDGF-和IL-11介导的激活，2）确定HASMC中Stat诱导的增殖和3）的机制，以检查ASM在AIRWAY AIRWAY AIRWAY REMODELEDERITID的两种不同动物模型中JAK-STAT途径在ASM增殖中的作用。预计这些研究将有助于我们理解哮喘中慢性气道炎症和随后的重塑的机制，并可能为这种常见和令人衰弱的肺部疾病提供新颖的治疗策略。