G-PROTEIN COUPLED RECEPTORS IN ASTHMA AND INFLAMMATION

肥大细胞是一种多功能免疫细胞，在过敏性和炎症性疾病中发挥重要作用。这些细胞通过细胞表面高亲和力IgE受体(FCepsilonRI)的交联性激活，导致组胺的爆炸性释放和脂质衍生介质的产生。最近的研究表明，激活的肥大细胞还能产生多种细胞因子和趋化因子。白细胞的募集和激活，如嗜碱性粒细胞和嗜酸性粒细胞，通过激活趋化因子受体，介导肥大细胞的许多功能。这项工作的一个重要假设是，肥大细胞/嗜碱性粒细胞的反应状态受其他炎症介质的调节，如过敏毒素、C3pha和细胞因子/趋化因子。除了它们的信号转导途径外，人们认为这些调节剂还调节肥大细胞和嗜碱性粒细胞上存在的其他受体的活性。这个实验室已经开发出一种嗜碱性和肥大细胞系，可以进行遗传操作、生化和功能分析。利用这些系统，我们已经证明了C3a受体的激活增强了(Primes)抗原刺激的介质释放。我们的研究还发现，C3a和其他G蛋白偶联受体在引起脱颗粒和支持趋化因子基因表达方面的能力存在意想不到的差异。我们假设这些差异反映了这些受体在磷酸化和脱敏方面的差异。将在此进行的研究将使我们对肥大细胞/嗜碱性粒细胞功能调节和交叉调节的机制有一个准确的了解。这项工作将扩大我们对肥大细胞/嗜碱性粒细胞在疾病过程中作用的分子基础的理解。此外，这可能会为哮喘和其他炎症性肺部疾病的发展提供更好的理论基础。

Mast cells are multifunctional immune cells that play essential roles in allergic and inflammatory diseases. Activation of these cells via the cross-linking of cell surface high-affinity IgE receptors (FCepsilonRI) leads to the explosive release of histamine and generation of lipid-derived mediators. Recent studies demonstrated that activated mast cells also produce a variety of cytokines and chemokines. Recruitment and activation of leukocytes such as basophils and eosinophils, via the activation of chemokine receptors, mediate many functions of mast cells. An important hypothesis of the work described herein is that the state of mast cell/basophil responsiveness is regulated by other inflammatory mediators such as the anaphylatoxin, C3alpha and cytokines/chemokines. In addition to their signal transduction pathways, it is proposed that these modulators regulate the activity of other receptors present on mast cells and basophils. This laboratory has developed a basophilic and a mast cell line that are amenable to genetic manipulation and biochemical as well as functional analysis. Using these systems, we have demonstrated that activation of C3a receptors enhances ( primes ) antigen-stimulated mediator release. Our studies also revealed unexpected differences in the ability of C3a and other G protein coupled receptors to cause degranulation and support chemokine gene expression. We hypothesize that these differences reflect differences in phosphorylation and desensitization of these receptors. The studies to be performed herein will give us a precise understanding of the mechanisms by which by which mast cell/basophil functions are regulated and cross-regulated. This work will broaden our understanding of the molecular basis for the roles of mast cell/basophils in disease processes. In addition, it will likely provide a better rationale for the development of asthma and other inflammatory lung diseases.