Thrombocytopenia is one of the life threatening hematologic disorders that may occur as a result of autoimmune process or during the asymptomatic and clinical stage of HIV-1 infection. It is hypothesized that disruption of chemokine network, and adhesive interactions between megakaryocytes (MKs) and bone marrow endothelium (BMEC) as it may occur during HIV infection, plays a seminal role in the failure of MK transmigration and platelet release. The exact mechanism and site of platelet formation is not well defined. Studies have shown that transmigration of MK through BMEC, may be critical for platelet formation. The investigators have discovered that mature polypoid MKs express the chemokine receptor (HIV co-receptor): CXCR4. Stromal Derived Factor 1 (SDF1) which is the ligand for the CXCR4, promotes transmigration of MKs through BMEC monolayers. They have also identified a novel endothelial cell derived factor (ECDF1) that selectively induce migration of MKs through BMEC. Transendothelial migration of MKs in response to SDF1 or ECDF1 enhances formation of functional platelets. Interaction of migration MK with adhesion molecules expressed on MBEC such as E-selectin and PECAM is critical for MK migration and optimal platelet formation. They have also discovered that HIV can inject MKs through CXCR receptor, interfering with transendothelial migration of Mks, and platelet release. In this proposal they plan to 1) Define the mechanism whereby SDF1 and ECDF1 modulate adhesion molecule adhesion molecule expression of MK and BMEC cells. 2) Characterize cellular signaling pathways such as apoptotic pathways that may be induced by transmigration of Mks. 3) Take advantage of the availability of MK and BMEC derived from E-selectin knockout mice to study the role of these factors in regulation of CXCR expression. Both MKs and BMEC express CD4 and CXCR4, and are therefore susceptible to HIV infection. Therefore, it is planned to define the mechanism whereby HIV infection of either Mks and BMEC may influence chemokine receptor, and adhesion molecule expression resulting in dysfunction or platelet formation. Whether HIV-1 gp120 or other factors including megakaryopoietins that interact with CXCR4 may also influence platelet formation will also be explored. They plan to over-express CXCR4 and SDF1 within the milieu of marrow microenvironment by adenoviral vectors to explore the possibility of augmenting platelet production. This project should lead to the definition of the role of chemokines and adhesion molecules expressed by BMEC that regulate platelet production. Identification of chemokine receptors that may regulate platelet production may elucidate pathogenesis of thrombocytopenia in HIV or other thrombocytopenic states and suggest potential pharmacological interventions. Modulation of chemokine receptors expression by adenoviral vectors overexpressing SDF1, ECDF1 or their receptors may allow for developing therapies to ameliorate thrombocytopenia in vivo.
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