Asthma and allergic disease are major public health problems. The recruitment and activation of eosinophils in the airways play a pivotal role in the pathogenesis of these diseases. Recent studies suggest that CC chemokines such as eotaxin, RANTES, MCP-3, and MCP-4 are important eosinophil chemoattractants. The chemotactic responses of eosinophils is mostly mediated by the CC chemokine receptor-3 (CCR3), which is also expressed on Th2 cells and basophils. CCR3 is a co-receptor for macrophage-tropic human immunodeficiency virus (HIV). The signaling mechanisms of CCR3 is unknown. The goal of this research project is delineate the signal transduction mechanism of CCR3 leading to eosinophil chemotaxis. The hypothesis of the proposal is that the MAP kinase signaling pathway plays a critical role in CCR-3 mediated eosinophil chemotaxis. We postulate that ERK2 and p38 MAP kinases activate myosin light chain kinases, which stimulates myosin II. The ATPase activity of myosin II is critical for generation of energy for locomotion. The p38 MAP kinase is additionally important for cellular adhesion and lamellipod formation.
Specific Aim 1 will examine the activation of ERK, JNK and p38 MAP kinases in eotaxin-stimulated eosinophils and will establish their functional relevance.
Specific Aim 2 will dissect the mechanism by MAP kinases regulated four phases of chemotaxin, i.e. lamellipod formation, adhesion, traction, and de- adhesion.
Specific Aim 3 will investigate the importance of MAP kinases in the activation of myosin light-chain kinase and myosin II. Finally, Specific Aim 4 will address the importance of MAP kinases in airway eosinophil recruitment in vivo. We have previously delineated major signaling pathways of IL-5 using eosinophils. Thus, we have the necessary expertise to perform signaling studies in eosinophils. The research proposal has important basic science and clinical implications. The delineation of the molecular mechanism of eotaxin action will advance basic knowledge. The identification of critical signaling molecules of CCR3 will help design novel therapeutic targets for asthma and allergic diseases. Eosinophil activation is the central theme of the center grant application. The signaling studies of this project will complement and enhance similar components of other projects and is likely to yield synergistic effects.
Showing the most recent 10 out of 20 publications
