Hematopoietic-derived cell-cell interaction occurs through specific surface adhesion proteins, including the integrins and selectins, and is critical for circulatory homeostatic processes, inflammation, and hemostasis. Our laboratory has investigated leukocyte-platelet adhesion with particular reference to: (A) the characterization of activated and unactivated platelet adhesion to resting neutrophils and monocytes; (B) identification of the leukocyte ligands on activated platelets; (C) the relative affinities of platelet-heterotypic and homotypic cell adhesion; and (D) the significance of increased lymphocyte-platelet binding in bone marrow transplant (BMT) patients with graft versus host disease (GVHD). These studies, coupled with clinical observations and the potential role of adhesion receptors in the balance between GVHD and graft rejection, provide a basis for the study of normal and pathologic physiology of leukocyte- platelet interactions which will serve as the core agenda for this physician-scientist award application. This application also provides a detailed training program for the applicant in bench investigation of cell- cell interactions using functional cell biology assays, molecular approaches to identification and characterization of cell receptors, and comprehensive immunology and fluorescence techniques. The core research project will employ an extensive didactic and directed bench research agenda with the objective of developing a fully independent physician- investigator. Using both conventional assays and unique systems developed in our laboratory, we propose in phase I of this award to: (1) identify leukocyte and platelet subsets capable of adhesion and the responsible receptor-ligand pairs; (20 investigate the identity of the leukocyte receptor for unactivated platelet adhesion by molecular biological techniques; (3) explore the functional consequences of leukocyte-platelet adhesion with respect to transmembrane signal transduction, superoxide generation by phagocytes, and intercellular transfer of small molecular weight dyes between leukocytes and platelets; (4) determine the effects of cytokines prevalent post-BMT on leukocyte-platelet binding; and (5) in phase II, determine the perturbations in such cellular interactions in the post-transplant setting, with particular attention to GVHD. Understanding the cellular and molecular basis of this pathology may allow directed strategies at ameliorating BMT complications.
Showing the most recent 10 out of 14 publications
