Investigation of adhesive properties and signaling pathways of neutrophils and platelets and their role in inflammatory diseases

Abstract

Our previous studies have established that increased leukocyte and red cell adhesive properties may play an important role in sickle cell disease (SCD), a condition characterized by a chronic inflammatory state. In the current project, we aim to further understand the signaling pathways involved in neutrophil adhesion and how alterations in these pathways may participate in inflammation. Furthermore, we plan to broaden our studies by looking at the role of platelet adhesion in SCD and also to initiate studies to investigate the role of neutrophil adhesion and signaling pathways involved in another classic inflammatory disease, rheumatoid arthritis (RA). Our data suggest that increased neutrophil adhesion in SCD may be mediated by alterations in the cAMP/cAMP-dependent protein kinase (PKA) pathway. Since very little is known about the role of cAMP-PKA signaling in leukocyte adhesion, the first part of this study aims to investigate the effect of the upregulation of the CAMP/PKA pathway on normal neutrophil adhesion molecule expression and adhesive properties. Secondly, our preliminary data suggest that platelet adhesive properties may be augmented in SCD, thus, we plan to further investigate this finding by comparing the adhesion molecule expression and adhesive properties of platelets from SCD and control individuals and, once again, investigate a possible role for cyclic nucleotide signaling in this altered adhesion. Finally, building on our studies demonstrating the role of leukocyte and red cell adhesive properties in SCD inflammation, we plan to broaden our studies by investigating the expression and function of adhesion molecules on the neutrophils of patients with RA, since neutrophils are found in abundance in the synovial fluid of these individuals and plan a fundamental role in this disease. We plan, also, to look at adhesion molecule expression and function during the in vitro neutrophilic differentiation of hematopoietic CD34+ stem cells from these individuals. In conclusion, this study will further the understanding of the role of the adhesion of neutrophils and platelets in inflammatory diseases and define some of the signaling pathways that may be involved in these processes. Such an understanding will allow the identification of novel drug targets for the treatment of diseases characterized by a chronic inflammatory state. (AU)