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（MCs）可以有直接和间接的作用，可以显著增强气道中抗原（Ag-）诱导的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。具体来说，我们假设，在涉及肺部的急性或慢性过敏性炎症的某些小鼠模型中，抗体（Ab-）依赖性和抗体非依赖性机制的MC激活导致净效应，这些净效应可以显著促进炎症的发展和/或增强，气道高反应性（AHR）和与这些“哮喘模型”相关的组织重塑。许多这样的作用是由MC相关的TNF促进的，并且可以通过干扰素γ (IFNgamma)增强，干扰素γ通过干扰素γ受体（IFNgammaRs）作用于MC。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。我们将研究基因MC缺陷的c-kit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c-kit突变小鼠，这些小鼠被选择性地植入了WT MCs或表达基因决定的异常产物的MCs，我们假设这些产物参与了MC功能的激活、调节或调解。通过评估这些哮喘模型的关键特征在c-kit突变型mc缺陷小鼠和WT小鼠中的差异程度，我们可以量化这些反应对c-kit的依赖性。通过确定c-kit突变小鼠中反应表达的异常在多大程度上被“正常化”或以其他方式改变，当这些小鼠被选择性地植入WT或基因操纵的MCs时，我们可以评估MCs以及单个MC产物，包括膜相关或可溶性TNF， IFNgammaR1或某些G蛋白偶联受体，对这些反应特征的表达的贡献。通过更好地了解MCs促进小鼠哮喘模型重要特征发展的机制，以及影响MCs在这些环境中被激活表达其功能的程度的机制，我们将拓宽MCs在人类哮喘发展和进展中的潜在作用的视野，并可能为这种疾病的治疗提供新的方法。

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.