BLOOD MONOCYTE RECEPTOR EXPRESSION AND MODULATION

单核/巨噬细胞FcGamma受体在宿主防御中起重要作用 几种血液病的病理生理学。增强其功能 活动促进了这些细胞消除 微生物。抑制它们的活性可以改善临床状态 患有自身免疫性溶血性贫血和血小板减少症的患者。那里 在FcGamma受体和三个截然不同的 单核/巨噬细胞FcGamma受体蛋白，FcGammaRI(CD64)，FcGammaRII (CD32)和FcGammaRII(CD16)，已在MAN中定义。相当多的数据 我们实验室和其他实验室的研究人员帮助解释了这一数字 在单核/巨噬细胞上的这些受体中，它们与免疫球蛋白G配体的亲和力 以及它们在体外和体内的调节。然而，它的意义在于 每种单核/巨噬细胞FcGamma受体及其功能 几乎是未知的。我们在这项研究计划中的目标是 描绘不同单核/巨噬细胞之间的相互关系 试图理解为什么这些细胞有更多的 而不是一个FcGamma受体。我们将特别关注 结合单体免疫球蛋白的受体FcGammaRI的潜在作用。 具体来说，我们将探讨以下问题：1)关系 单核细胞FcGamma受体之间的相互作用。我们将建立 单核细胞FcGammaRI与FcGammaRII或 并将研究FcGammaRI的扰动对 FcGammaRII及FcGammaRI在培养细胞从头表达中的作用 单核细胞FcGammaRIII。我们的假设是占用或交叉连接 FcGammaRI影响这些过程。2)各FcGamma受体在 重要的单核细胞功能。激活每个FcGamma的效果 细胞内钙、超氧阴离子产生和细胞内钙受体的变化 将研究溶酶体酶的释放。我们的假设是 每个FcGamma受体的激活导致定量或 本质上不同的功能程序。转基因研究将 检验细胞质结构域对 FcGammaRI的信号转导。3)。单核细胞之间的关系 FcGammaRI对FcGammaRII和FcGammaRIII的作用。假设是为了 需要检验的是，FcGammaRI的扰动调制了泛函 由激活FcGammaRII和FcGammaRIII介导的程序。4)我们会 还定义了一种调节FcGamma受体的介体的作用 单核细胞FcGammaRI的活性，Hageman因子。5)最后，我们会 检测FcGamma受体在已建立的 使我们能够专注于差分调制的实验模型 这些受体在体内的作用。

Monocyte/macrophage Fcgamma receptors are important in host defense and in the pathophysiology of several hematologic diseases. Enhancement of their activity facilitates the ability of these cells to eliminate microorganisms. Inhibition of their activity improves the clinical status of patients with autoimmune hemolytic anemia and thrombocytopenia. There is substantial heterogeneity among the Fcgamma receptors and three distinct monocyte/macrophage Fcgamma receptor proteins, FcgammaRI (CD64), FcgammaRII (CD32) and FcgammaRII (CD16), have been defined in man. Considerable data from our laboratory and that of others have helped to elucidate the number of these receptors on monocytes/macrophages, their affinity for IgG ligand and their modulation in vitro and in vivo. However, the significance of each monocyte/macrophage Fcgamma receptor and the function each subserves are virtually unknown. Our goals in this research proposal are to delineate the interrelationships between the different monocyte/macrophage Fcgamma receptors in an attempt to understand why these cells have more than one Fcgamma receptor. We will give particular attention to the potential role of FcgammaRI, the receptor which binds monomeric IgG. Specifically, we will explore the following questions: 1) The relationship of the monocyte Fcgamma receptors to one another. We will establish whether monocyte FcgammaRI is topographically related to FcgammaRII or FcgammaRIII and will examine the effect of perturbation of FcgammaRI on FcgammaRII and the role of FcgammaRI in the de novo expression of cultured monocyte FcgammaRIII. Our hypothesis is that occupancy or cross-linking of FcgammaRI affects these processes. 2) The role of each Fcgamma receptor in important monocyte functions. The effect of activation of each Fcgamma receptor on changes in intracellular Ca++, superoxide generation and lysosomal enzyme release will be studied. Our hypothesis is that activation of each Fcgamma receptors leads to quantitatively or qualitatively different functional programs. Transfection studies will examine the hypothesis that the cytoplasmic domain is critical to the signal transduction of FcgammaRI. 3). The relationship of monocyte FcgammaRI to the function of FcgammaRII and FcgammaRIII. The hypothesis to be tested is that perturbation of FcgammaRI modulates the functional programs mediated by activation of FcgammaRII and FcgammaRIII. 4) We will also define the effect of one mediator which modulates Fcgamma receptor activity, Hageman factor, on monocyte FcgammaRI. 5) Finally, we will examine the regulation of the Fcgamma receptors in an established experimental model which enables us to focus on the differential modulation of these receptors in vivo.