Understanding the role of Tec in Fcgamma receptor mediated phagocytosis

特异性免疫细胞（巨噬细胞）对细菌病原体和其他外来颗粒的识别和破坏主要由Fc γ类细胞表面抗体受体介导。这项提议旨在了解将受体激活与细胞重排联系起来的分子机制，这些细胞重排是内陷或吞咽冒犯性颗粒所必需的。我们已经使用免疫荧光显微镜和生物化学方法表明，细胞内酪氨酸激酶Tec是一个重要的组成部分的吞噬机制。本研究计划利用高选择性基因打靶技术建立一个不含Tec蛋白的小鼠细胞培养模型系统。这将使我们能够确定Tec是否是Fc γ介导的吞噬作用所必需的。将突变形式的Tec蛋白重新引入到这种空背景中将提供关于Tec的分子伴侣和Tec蛋白内各个结构域的个体作用的详细信息。通过研究吞噬作用的分子机制，我们期望了解如何影响Fc γ信号通路，以增强处理病原体的能力，或限制与自身免疫性疾病相关的过度吞噬的后果。Tec是一种可能在Fc γ受体和肌动蛋白细胞骨架重排之间发挥重要作用的酶，因此是一种潜在的重要药物靶标。

The recognition and destruction of bacterial pathogens and other foreign particles by specific immune cells (macrophages) is principally mediated by the Fcgamma class of cell surface antibody receptors. This proposal aims to understand the molecular mechanisms which link receptor activation to the cellular rearrangements required to invaginate or swallow the offending particle. We have used immunofluorescent microscopy and biochemical methods to show that the intracellular tyrosine kinase Tec is an important component of the phagocytosis mechanism. Here we plan to use highly selective gene targeting methods to generate a mouse cell culture model system which is devoid of Tec protein. This will allow us to determine whether Tec is essential for Fcgamma-mediated phagocytosis. Reintroduction of mutant versions of the Tec protein into this null background will provide detailed information on the molecular partners of Tec and the individual roles of the various domains within the Tec protein. By studying the molecular mechanism of phagocytosis, we expect to gain an understanding of how to influence the Fcgamma signalling pathway, either to enhance the ability to deal with pathogens, or to restrict the consequences of excessive phagocytosis associated with autoimmune diseases. Tec is an enzyme likely to play an important role between the Fcgamma receptor and actin cytoskeleton rearrangements and therefore is a potentially important drug target.