BLOOD MONOCYTE RECEPTOR EXPRESSION AND MODULATION

单核细胞/巨噬细胞Fc γ受体在宿主防御和免疫应答中是重要的。 几种血液病的病理生理学。 增进两国 活性促进这些细胞的能力， 微生物的 抑制其活性可改善临床状态 自身免疫性溶血性贫血和血小板减少症的患者。 那里 Fc γ受体之间存在实质性异质性， 单核细胞/巨噬细胞Fc γ受体蛋白，Fc γ RI（CD 64），Fc γ RII 已经在人类中定义了Fc γ RII（CD 32）和Fc γ RII（CD 16）。 我们和其他人的实验帮助我们阐明了 单核细胞/巨噬细胞上的这些受体，其对IgG配体的亲和力 以及它们在体外和体内的调节。 然而， 每种单核细胞/巨噬细胞Fc γ受体及其各自的功能 几乎无人知晓 本研究计划的目标是 描绘不同单核细胞/巨噬细胞之间的相互关系 Fc γ受体，试图了解为什么这些细胞有更多的 一个Fc γ受体。 我们将特别注意 Fc γ RI（结合单体IgG的受体）的潜在作用。 具体而言，我们将探讨以下问题：1）关系 单核细胞Fc γ受体的相互作用。 我们将建立 单核细胞Fc γ RI是否与Fc γ RII地形相关， FcgammaRIII的干扰，并将检查FcgammaRIII的干扰的影响。 FcgammaRII和FcgammaRI在体外培养的大肠杆菌中的从头表达中的作用 单核细胞Fc γ RIII。 我们的假设是， Fc γ RI影响这些过程。 2)每种Fc γ受体在以下中的作用 重要的单核细胞功能。 每种Fc γ的活化的影响 受体对细胞内Ca++、超氧化物生成和 将研究溶酶体酶释放。 我们的假设是 每种Fc γ受体的活化导致定量或 不同功能的程序。 转染研究将 检查假设，即胞质结构域是至关重要的 Fc γ RI信号转导。 3）。 单核细胞的关系 Fc γ RI对Fc γ RII和Fc γ RIII的功能的影响。 假设， FcgammaRI的扰动调节了功能性 通过激活Fc γ RII和Fc γ RIII介导的程序。 4)我们将 还定义了一种调节Fc γ受体的介质的作用 Hageman因子对单核细胞Fc γ RI的活性。 5)最后我们将 检查Fc γ受体在已建立的 实验模型，使我们能够专注于差分调制 这些受体在体内。

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.