Many biologically active molecules, including hormones, neurotransmtters, prostaglandin, and chemoattractants that include chemokines, transduce their signals by interacting with heterotrimeric G proteins. Thus, G protein-mediated signal transduction plays important roles in a variety of biological processes, ranging from neuronal activities, metabolism, homeostasis, the inflammatory responses, some of the sensory processes and regulation of growth and differentiation. Some of these signal transduction pathways, when they go wrong, cause pathological consequences. Our long-term goal is to understand the molecular basis and function of G protein-mediated signal transduction. In this renewal proposal, we will continue our study of the molecular basis and function of chemoattractant-activated signal transduction pathways. Chemoattractants are believed to act as immediate mediators of inflammatory responses and transduce their signals primarily through the Gi class of G proteins. We have carried out comprehensive characterization of two chemoattractant-activated phospholipid-signaling pathways that are mediated by PLC about32/I33 and PI3Ky in transfected cells and in leukocytes isolated from transgenic mice. These studies not only provided informative insights into the roles of these pathways in leukocyte function, but also revealed many intriguing and important questions. In this renewal proposal, we intend to investigate three of these questions: 1) We will determine the mechanisms for the enhanced responses associated with PLC-deficiencies; 2) We will use a combination of transfection, biochemical and transgenic approaches to investigate a novel chemoattractant-activated signaling pathway that is mediated by p21 -activated protein kinase and elucidate the roles of this pathway in leukocyte function; and 3) We will determine the primary sites of defects that are responsible for the systemic phenotypes associated with PLC B3 or PI3Ky deficiency by generating and studying additional transgenic mouse lines. We believe that these proposed studies will not only further our understanding of the roles of G protein-mediated signaling pathways in the development and function of leukocytes, but also may reveal potential targets for developing novel therapeutic agents and strategies to combat inflammatory reactions.
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