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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Physician Scientist Award (K11)
Project #
5K11HL002668-02
Application #
3087846
Study Section
Research Manpower Review Committee (MR)
Project Start
1992-09-30
Project End
1997-09-29
Budget Start
1993-09-30
Budget End
1994-09-29
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Rinder, C S; Rinder, H M; Johnson, K et al. (1999) Role of C3 cleavage in monocyte activation during extracorporeal circulation. Circulation 100:553-8
Rinder, C S; Rinder, H M; Smith, M J et al. (1999) Selective blockade of membrane attack complex formation during simulated extracorporeal circulation inhibits platelet but not leukocyte activation. J Thorac Cardiovasc Surg 118:460-6
Rinder, H M; Tracey, J B; Recht, M et al. (1998) Differences in platelet alpha-granule release between normals and immune thrombocytopenic patients and between young and old platelets. Thromb Haemost 80:457-62
Rinder, H M; Ault, K A (1998) Platelet activation and its detection during the preparation of platelets for transfusion. Transfus Med Rev 12:271-87
Rinder, H M; Schuster, J E; Rinder, C S et al. (1998) Correlation of thrombosis with increased platelet turnover in thrombocytosis. Blood 91:1288-94
Smith, B R; Rinder, H M (1997) Interactions of platelets and endothelial cells with erythrocytes and leukocytes in thrombotic thrombocytopenic purpura. Semin Hematol 34:90-7
Rinder, C S; Mathew, J P; Rinder, H M et al. (1997) Lymphocyte and monocyte subset changes during cardiopulmonary bypass: effects of aging and gender. J Lab Clin Med 129:592-602
Peterec, S M; Brennan, S A; Rinder, H M et al. (1996) Reticulated platelet values in normal and thrombocytopenic neonates. J Pediatr 129:269-74
Tracey, J B; Rinder, H M (1996) Characterization of the P-selectin ligand on human hematopoietic progenitors. Exp Hematol 24:1494-500
Harris, S N; Rinder, C S; Rinder, H M et al. (1995) Nitroprusside inhibition of platelet function is transient and reversible by catecholamine priming. Anesthesiology 83:1145-52

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