Grant: Operating Grant

Background: The microbicidal functions of neutrophils (PMN) are highly dependent on their ability to migrate from the vasculature into infected sites. This directed migration, or chemotaxis, involves two key steps: 1) compass-like sensing of the chemoattractant gradient; and 2) actin assembly in the leading lamella mediated through the actin binding protein cofilin, which drives cell migration towards the chemoattractant. Rho family small GTPases including Rac, Rho and Cdc42, are important regulators of cell migration that impact health and disease. For example, patients with a Rac2 mutation exhibit a severe PMN chemotactic defect and experience life threatening bacterial infections. Severe PMN chemotactic defects typify Rac1 and Rac2 null mice, experimental models which we developed to study Rac isoform function in PMNs. Goal: Define how these highly homologous Rac proteins carry out their unique signaling roles during PMN chemotaxis and recruitment to sites of infection. Significance: The transgenic mouse models and the combination of novel techniques used in this grant will permit biochemical and functional examination of the local signaling roles played by Rac1 and Rac2 and their downstream ROS activated signaling elements in actin-mediated PMN chemotaxis. Over the long-term, this knowledge will allow us to identify key downstream mediators of PMN recruitment to sites of infection and inflammation. By better understanding the signaling elements involved in the key aspects of PMN chemotaxis we will be able to translate this information into more specific and promising anti-inflammatory drugs.