SCF in Allergic Airway Inflammation

描述（由申请人提供）：支气管周围白细胞的积累和激活是哮喘气道反应发展过程中的一个主要疾病因素，导致慢性气道疾病。特别是，嗜酸性粒细胞已被报道为与支气管损伤诱导相关的主要人群，并被认为参与上皮细胞损伤、粘液产生、支气管阻塞和气道高反应性。在过去的几年里，我们的实验室一直在研究在蟑螂过敏原诱导的反应中，气道中产生的干细胞因子（SCF）的新作用。我们的数据提供了与诱导过敏反应直接相关的新发现。当SCF在气道内被中和时，可以观察到与嗜酸性粒细胞积累、嗜酸性粒细胞激活和粘液产生直接相关的长期变化。后一个方面将是这个更新申请的重点，研究集中在一个主要概念上。我们的假设是，蟑螂过敏原攻击后，气道内SCF的气道上皮细胞产生激活募集的嗜酸性粒细胞，上调炎症和生长因子，从而诱导气道高反应性和粘液产生增加。SCF产生上皮细胞和浸润性嗜酸性粒细胞之间的复杂相互作用将通过建立变应性气道疾病的体内模型和体外分析来研究，以更好地确定反应的机制。为了验证这一假设，我们将重点研究气道上皮细胞衍生的SCF诱导特定嗜酸性粒细胞相关功能的机制。我们的研究将1)确定SCF有助于慢性气道疾病的发展，并确定其与嗜酸性粒细胞积累和激活以及粘液产生的关系，2)确定SCF通过何种信号转导途径影响嗜酸性粒细胞激活，从而导致气道中随后的粘液产生。3)确定特定途径在SCF诱导的功能中具有特定作用，从而导致粘液产生的激活；4)研究上皮细胞来源的SCF如何影响嗜酸性粒细胞的激活；5)确定SCF激活的嗜酸性粒细胞改变粘液相关基因和蛋白质发育的机制。为了评估scf诱导的嗜酸性粒细胞激活导致气道损伤、粘液产生和病理生理的机制，我们将解决一些以前未探索的机制。我们将特别关注那些与导致嗜酸性粒细胞激活和特定炎症和粘液产生细胞因子的差异SCF信号有关的问题。此外，我们将评估正常和SCF缺乏过敏小鼠气道生理学的变化，并阐明慢性疾病发展过程中SCF诱导的嗜酸性粒细胞激活导致粘液过量产生的机制。我们的研究还将利用siRNA结构的新技术来抑制scf诱导的嗜酸性粒细胞活化的特定方面。

DESCRIPTION (provided by applicant): Peribronchial leukocyte accumulation and activation is a major disease factor during development of asthmatic airway responses that leads to chronic airway disease. In particular, eosinophils have been reported to be primary populations associated with induction of bronchial injury, and are thought to participate in epithelial cell damage, mucus production, bronchial obstruction, and airway hyperreactivity. Over the past several years our laboratory has been investigating the novel role of stem cell factor (SCF) produced in the airway during cockroach allergen-induced responses. Our data has provided novel findings related directly to the induction of the allergic responses. When SCF is neutralized within the airway long-term changes can be observed related directly to eosinophil accumulation, eosinophil activation, and mucus production. This latter aspect will be the focus of this renewal application with studies centered on a principal concept. Our hypothesis is that airway epithelial cell production of SCF within the airway after cockroach allergen challenge activates recruited eosinophils upregulating inflammatory and growth factors that induce increased airway hyperreactivity and production of mucus. This complex interaction between SCF producing epithelial cells and infiltrating eosinophils will be investigated using both an established in vivo model of allergic airway disease and in vitro analysis to better identify the mechanism of the responses. To test this hypothesis we will focus on mechanisms involved in the ability of airway epithelial cell-derived SCF to induce specific eosinophil related functions. Our studies will 1) establish that SCF contributes to the development of chronic airway disease and define its relation to eosinophil accumulation and activation as well as mucus production, 2) define by what signal transduction pathways SCF influences eosinophil activation leading to subsequent mucus production in the airway, 3) determine that particular pathways have a specific role for SCF-induced functions leading to activation of mucus production 4) investigate how epithelial cell-derived SCF impacts on eosinophil activation, and 5) define by what mechanism SCF-activated eosinophils alter development of mucus-related genes and protein. To assess the mechanisms of SCF-induced eosinophil activation leading to airway damage, mucus production, and pathophysiology, we will address a number of previously unexplored mechanisms. We will especially concentrate on those pertaining to differential SCF signaling leading to eosinophil activation and specific inflammatory and mucus producing cytokines. In addition, we will assess changes in airway physiology in normal and SCF deficient allergic mice and elucidate the mechanism of SCF-induced eosinophil activation during chronic disease development leading to mucus overproduction. Our studies will also utilize new technology with siRNA constructs for inhibition of specific aspects of SCF-induced eosinophil activation.