Expression and Modulation of Mast Cell Function in Asthma

描述(由申请人提供)：我们假设肥大细胞(MC)可以具有直接和间接的作用，可以显著增强抗原(Ag)诱导的呼吸道炎症反应的局部发展，以及这种过程在肺部的结构和功能后果。具体地说，我们假设，在某些涉及肺部的急性或慢性变态反应性炎症小鼠模型中，抗体(Ab)依赖和抗体非依赖的机制激活MC会产生净效应，这可以显著促进与这些“哮喘模型”相关的炎症、气道高反应性(AHR)和组织重构的发展和/或增强，并且许多这样的效应是由MC相关的肿瘤坏死因子促进的，并可以通过干扰素-γ受体(IFNGammaRs)作用于MC而增强。我们将通过使用不同的方案来测试这些假设，这些方案可以在小鼠中引发急性或慢性哮喘模型。我们将检测c-kit基因缺陷突变小鼠(WBB6F1-KitW/W-v小鼠和C57BL/6-KitW-sh/W-sh小鼠)同源Kit+/+野生型(WT)小鼠和“MC敲入小鼠”，即选择性地植入WT MCs或MCs的c-kit突变小鼠，这些小鼠表达基因决定的异常表达的产物，我们假设这些产物参与MC功能的激活、调节或调节。通过评估这些哮喘模型的关键特征在c-kit突变MC缺陷小鼠和wt小鼠中的不同程度，我们可以量化c-kit反应的依赖性。通过确定当c-kit突变小鼠被选择性地植入WT或基因操纵的MC时，这些小鼠反应中的任何异常表达被“正常化”或以其他方式改变到什么程度，我们可以评估MC以及单个MC产品对这些反应特征的表达的贡献，包括膜相关或可溶性的肿瘤坏死因子、IFNGammaR1或某些G蛋白偶联受体。通过更好地了解MCs促进小鼠哮喘模型重要特征的发展的机制，以及影响MCs在这些环境中被激活以表达其功能的程度的机制，我们将拓宽MCs在人类哮喘发生发展中的潜在作用的观点，并可能提出治疗这种疾病的新方法。

DESCRIPTION (provided by applicant): We hypothesize that mast cells (MCs) can have direct and indirect effects which can significantly enhance the local development of antigen- (Ag-) induced inflammatory responses in the airways, as well as the structural and functional consequences of such processes in the lungs. Specifically, we hypothesize that, in certain mouse models of acute or chronic allergic inflammation involving the lungs, MC activation by both antibody- (Ab-)dependent and Ab-independent mechanisms results in net effects which can contribute significantly to the development and/or enhancement of the inflammation, airway hyperreactivity (AHR) and tissue remodeling associated with these "asthma models", and that many such effects are promoted by MC- associated TNF and can be enhanced by interferon gamma (IFNgamma), acting via IFNgamma receptors (IFNgammaRs) on MCs. We will test these hypotheses by using different protocols that can elicit either acute or chronic models of asthma in mice. We will examine genetically MC-deficient c-kit mutant mice (WBB6F1-KitW/W-v mice and C57BL/6- KitW-sh/W-sh mice) the congenic Kit+/+ wild type (WT) mice and "MC knock-in mice", i.e., c-kit mutant mice which have been selectively engrafted with WT MCs or MCs which express genetically-determined abnormalities in the expression of products which we hypothesize are involved in the activation, modulation or mediation of MC function. By assessing the extent to which key features of these asthma models differ in c-kit mutant MC-deficient and WT mice, we can quantify the c-kit-dependence of the responses. By determining to what extent any abnormalities in the expression of the responses in c-kit mutant mice are "normalized" or otherwise altered when such mice have been selectively engrafted with WT or genetically-manipulated MCs, we can assess the contribution of MCs, as well as individual MC products, including membrane-associated or soluble TNF, IFNgammaR1 or certain G protein-coupled receptors, to the expression of these features of the responses. By understanding better the mechanisms by which MCs can enhance the development of important features of asthma models in mice, and the mechanisms which influence the extent to which MCs can be activated to express their function in these settings, we will broaden the view of the potential roles of MCs in the development and progression of asthma in humans, and perhaps suggest new approaches for the management of this disorder.