The Effect of Lyn Deficiency on Mast Cell Activation and Inflammatory Disease Pro

肥大细胞在变态反应中的炎症功能是众所周知的，并且被怀疑参与了变态反应的发生。 其他自身免疫性疾病。看来维持肥大细胞内环境稳定对于防止肥大细胞增殖是至关重要的。 一系列炎症反应，但这种平衡是如何实现的还不清楚。最近我们发现 林恩KO小鼠表现出肥大细胞增生、嗜酸性粒细胞浸润和增强IgE和IgG受体 表达和信号传导。考虑到肥大细胞的炎症功能，我们假设林恩 缺乏导致慢性肥大细胞活化，导致嗜酸性粒细胞募集， 炎症性疾病。我们将直接测试肥大细胞在淋巴相关炎性疾病中的作用。 这些实验将提供一种新的手段接近肥大细胞相关疾病。 我们的具体目标是： I.明确林恩激酶在肥大细胞IgE和IgG受体表达和功能中的作用。 二.采用遗传学方法直接测量肥大细胞及其相关基因的重要性， 在Th 2炎症性疾病的发生和发展中的介质。 研究设计： 在目的I中，我们将在体外和体内模型中使用小鼠和人肥大细胞，以揭示林恩是如何在体内表达肥大细胞的。 缺乏会改变肥大细胞IgE和IgG受体的表达和功能。我们将特别关注 这些变化如何改变嗜酸性粒细胞和调节性T细胞的募集。我们还要确定林恩 在特应性患者中表达降低。 在Aim II中，我们将创建一系列双突变小鼠，以测量肥大细胞、IgE 和Fc γ RIII在由林恩缺乏引起的Th 2炎性疾病的发作和进展中的作用。我们 还将通过移植这些细胞来确定Lyn-deficient肥大细胞的必要作用和充分作用， 细胞移植到肥大细胞缺陷小鼠体内。 这些研究将通过我们在VCU的合作互动来补充。和斯皮格尔医生一起 Kepley和Schwartz，我们将把我们的工作扩展到人类肥大细胞。与康拉德博士林恩KO小鼠将 在哮喘模型系统中研究。此外，Spiegel和Chalfant博士将测试他们的小说的功效。 免疫抑制化合物对Lyn缺陷型肥大细胞作用。我们的研究将揭示 通过林恩激酶对炎症性疾病的作用，为治疗提供了新的途径。

Mast cells are well known for their inflammatory functions in allergy, and are suspected to participate in other autoimmune diseases. It appears that maintaining mast cell homeostasis is critical for preventing a range of inflammatory responses, but how this balance is achieved is not understood. Recently we found that Lyn KO mice exhibit mast cell hyperplasia, esoinophil infiltration and enhanced IgE and IgG receptor expression and signaling. Given the inflammatory functions of mast cells, we hypothesize that Lyn deficiency leads to chronic mast cell activation that results in eosinophil recruitment and subsequent inflammatory disease. We will directly test the role of mast cells in Lyn-associated inflammatory disease. These experiments will provide a novel means of approaching mast cell-associated disorders. Our Specific Aims are: I. To determine the role of Lyn kinase in mast cell IgE and IgG receptor expression and function. II. To employ genetic approaches to directly measure the importance of mast cells and their associated mediators in the onset and progression of Th2 inflammatory disease. Study Design: In Aim I, we will employ mouse and human mast cells in in vitro and in vivo models, to uncover how Lyn deficiency alters the expression and function of mast cell IgE and IgG receptors. We will specifically focus on how these changes alter eosinophil and regulatory T cell recruitment. We will also determine if Lyn expression is reduced in atopic patients. In Aim II, we will create a series of double mutant mice to measure the importance of mast cells, IgE and FcyRIII in the onset and progression of the Th2 inflammatory disease caused by Lyn deficiency. We will also determine the necessary versus sufficient role of Lyn-deficient mast cells by trasplanting these cells into mast cell-deficient mice. These studies will be complemented by our collaborative interactions at VCU. With Drs. Spiegel, Kepley and Schwartz, we will expand our work to human mast cells. With Dr. Conrad Lyn KO mice will be studied in an asthma model system. Further, Drs. Spiegel and Chalfant will test the efficacy of their novel immunosuppressive compound on Lyn-deficient mast cells. Our studies will reveal the contributions made by Lyn kinase to inflammatory disease and offer new avenues for therapy.