At the present time we are investigating the structure of the HSPGs which carry out the above inhibition, the precise manner by which suppression of SMC growth is achieved. We have little knowledge of how these biologic events are coordinately regulated. We have isolated the cDNA for an endothelial cell specific receptor temed thrombomodulin which helps to maintain the natural anticoagulant properties of the blood vessel wall. We have shown that the thrombomodulin gene is intronless and have defined protein-DNA interactions critical for transcriptional control of the gene. Several biologic systems are under study including an embroyologic system in which thrombomodulin gene transcription is initiated in concert with the appearance of other endothelial cell gene products as well as a cytokine induced suppression of thrombomodulin transcription in association with induction or suppression of other endothelial cell receptors and secreted proteins.
Megakaryocytes originate from stem cells of the bone marrow.
After completion of DNA synthesis, specific granules arise within megakaryocytes that contain cofactors which accelerate blood coagulation, adhesive proteins which facilitate cell-cell interactions, and growth factors which stimulate wound healing. Once cytoplasmic maturation has terminated, megakaryocytes fragment into small anucleate platelets which circulate within the blood. We have delineated molecular events which regulate megakaryocytopoiesis. Our knowledge of the PF4 gene is being employed to define the cellular pathway by which stem cells are committed to megakaryocytes as well as the subsequent steps of cytoplasmic maturation and fragmentation. Furthermore, we are using the above promoter to alter platelet cell surface receptors to investigate in vivo function as well as package different gene products within platelet alpha granules for controlled delivery to damaged areas of the cardiovascular system.