Certain proteins which participate in G-protein-based signaling are predominantly, if not exclusively, expressed in leukocytes and other hemopoietic cell types. For example, chemokine receptors are leukocyte-restricted receptors, G15 and G16 are leukocyte-specific members of the Gq G-protein family, and PI-PLC-beta-2 is a hemopoietic-specific homologue of the phospholipase C-beta family. The selective expression of such signaling proteins suggests that they are involved in biological functions unique to these blood cells. This application proposes to use transgenic and knockout mice models to explore the physiological roles of two leukocyte-specific signaling molecules: PI-PLC-beta-2 (PLCb2) and the interleukin-8 receptor (IL-8R). The first group of studies will examine several aspects of inflammatory responsiveness and hematopoiesis in mice lacking expression of PI-PLCb2. Particular emphasis will be placed on defining the in vivo role of this signaling protein on chemotactic responses, leukocyte homing and migration, activation of superoxide generation, and responses to viral infection. The second group of studies will utilize mice lacking expression of the IL-8 receptor as a null background for transgenic expression of mutant IL-8 receptor genes. Two types of mutant IL-8 receptors will be compared: IL-8 receptors, which exclusively activate pertussis toxin-sensitive Gi-family G-proteins, versus IL-8 receptors which exclusively activate pertussis toxin-insensitive G15/16 family G-proteins. Inflammatory responsiveness and hematopoiesis will be characterized in transgenic mice expressing these mutant receptors using methods and readouts similar to those used for the PLCb2 knockout mice.
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