Mechanisms and control of epithelial to mesenchymal transition in chronic asthma

慢性持续性哮喘与持续的气道炎症和气道重塑有关。 呼吸道炎症和重塑之间的关系仍然不确定；但有 有证据表明，皮质类固醇治疗不能阻止气道重塑的发展。因此，有 这是在更基本的水平上理解气道重塑发病机制的主要推动力。其中之一 气道重塑的关键成分是肌成纤维细胞的生成。肌成纤维细胞有助于 包括I型和III型胶原在内的基质蛋白的加速沉积以及 收缩装置。关于参与哮喘的肌成纤维细胞的起源，人们知之甚少。三 呼吸道肌成纤维细胞的潜在来源是驻留肺成纤维细胞的激活、骨的募集 骨髓成纤维细胞干细胞分化为成纤维细胞与呼吸道转化或转分化 上皮细胞转化为肌成纤维细胞。对其他器官，特别是肾脏的研究表明，上皮细胞 向间充质转化(EMT)是创伤或创伤后肌成纤维细胞的主要来源。我们的 假说认为慢性哮喘的呼吸道上皮细胞建立了一种局部环境，促进了 从上皮细胞到肌成纤维细胞，这是呼吸道重塑的重要组成部分。一个 这一假说的重要推论是，改变局部环境可以促进肌成纤维细胞向上皮化 过渡，从而改善重塑。 为了验证这一假设，我们提出了以下具体目标：1：评估潜在的机制 呼吸道上皮细胞上皮-间充质转化(EMT)；2)上皮间充质调控分析 3)探讨上皮间充质之间的关系。 慢性哮喘患者的转化和体内气道重塑。 这些研究将直接解决呼吸道可能经历的基本机制 慢性哮喘时的重塑。因为导致上皮细胞向间充质细胞转变的途径 受到当前和未来药物的调节，定义了在这一过程中的分子步骤 过渡将为未来限制改建的努力提供指导。最后，开发了一种生物标记物 重塑将显著增强监测这些治疗努力的能力。

Chronic persistent asthma has been linked to both ongoing airway inflammation and airway remodeling. The relationship between airway inflammation and remodeling has remained uncertain; but there is evidence that corticosteroid therapy does not prevent the development of airway remodeling. Thus, there is a major impetus to understand the pathogenesis of airway remodeling at a more fundamental level. One of the critical components of airway remodeling is the generation of myofibroblasts. Myofibroblasts contribute both to the enhanced deposition of matrix protein including types I and III collagens as well as to the contractile apparatus. Relatively little is known about the origin of myofibroblasts involved in asthma. Three potential sources of airway myofibroblasts are activation of resident lung fibroblasts, recruitment of bone marrow fibroblast stem cells that differentiate into fibroblasts and transition or transdifferentiation of airway epithelial cell into myofibroblasts. Studies in other organs, particularly the kidney, have shown that epithelial to mesenchymal transition (EMT) is a major source of myofibroblasts following injury or trauma. Our hypothesis is that airway epithelial cells in chronic asthma establish a local milieu that promotes transition of epithelial cells to myofibroblasts, and that this represents a significant component of airway remodeling. An important corollary of this hypothesis is that changing the local milieu can promote myofiblast to epithelial transition, and thereby improve remodeling. To test this hypothesis, we propose the following specific aims: 1: Assess the mechanisms underlying epithelial-mesenchymal transition (EMT) in airway epithelial cells; 2) Analyze the regulation of epithelialmesenchymal transition in airway epithelial cells; and 3) Explore the relationship between epithelialmesenchymal transition and in vivo airway remodeling in patients with chronic asthma. These studies will directly address a fundamental mechanism by which the airway may undergo remodeling during chronic asthma. Because the pathways leading to epithelial to mesenchymal transition are subject to regulation by current and future medications, defining the molecular steps in the process of transition will provide guidance for future efforts to limit remodeling. Finally, development of a biomarker for remodeling will significantly enhance the ability to monitor these therapeutic efforts.