Functional analysis of NO/cGMP- and PG-E1/cAMP-regulated signaling pathways in platelets and their precursor cells in chronic myeloid leukemia.
Project management at the University of Würzburg:
Myeloproliferative disorders are acute or chronic developing diseases derived from pluripotent stem cells in the bone marrow. Chronic myeloid leukemia (CML) is a frequent form, and patients with CML often show beside the proliferation of myeloid cells in bone marrow and blood, a functional defect in their platelets. Our project characterizes changes in cGMP- and cAMP-regulated signaling pathways in platelets and their precursor cells (CD34+ stem cells and megakaryocytes) of CML patients. In all (n=9) until now investigated CML patients identical changes in NO/cGMP-regulated signaling pathways could be found. Most prominently was a loss of cGMP-dependent protein kinase (cGMP-PK). Although these signaling pathways are known to regulate cell growth and cell differentiation in a variety of cell types, their function and regulation in platelet precursor cells is still unclear.We postulate that the selective loss of cGMP-PK in these cells contributes to the pathogenesis of CML and accompanying cardiovascular diseases. Therefore, we investigate proliferation, differentiation and gene expression in CD34+ stem cells and megakaryocytes of control persons and CML patients. These investigations will be complemented by the analysis of a mouse model with a deficient cGMP-signaling pathway (knock out of the cGMP-PK substrate VASP) that reveals megakaryocyte hyperplasia in the bone marrow. Characterization of these mechanisms might identify new therapeutical and diagnostic possibilities in hematologic, hemostatic and cardiovascular diseases.
Projekt period: from 07.2000 to 04.2004