C-MPL LIGAND IN HEALTH AND DISEASE

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There are six main objectives of this project: 1) to determine the physiologic and pathophysiologic regulation of the mpl ligand (TPO). Serum TPO levels will be determine for healthy volunteers as well as for individuals with numerous medical and surgical illnesses. This data will be used to determine the normal physiologic range of TPO, the range in pathologic states, the regulatory signals for TPO production and the organ(s) responsible for TPO production. These results will be important in developing clinical strategies for TPO administration. 2) to determine the effects of TPO administration on thrombocytopenic patients and platelet pheresis donors. These studies will involve giving TPO and determining the overall effects on platelet kinetics and platelet function,. This will include following platelet counts as well as performing bleeding times and platelet aggregometry. 3) to determine the impact of TPO administration on transfusion medicine. Platelet pheresis donors will be given TPO; consequently, platelet pheresis yield, survival of platelets in recipient and platelet function in recipients will be determined. TPO administration to patients with thrombocytopenia and to platelet pheresis donors is likely to result in decreasing the duration of life-threatening thrombocytopenia and increasing the benefit of platelet pheresis. 4) to evaluate TPO's role in bone marrow transplantation. Post-transplant TPO will be administered in attempt to decrease time to platelet engraftment and improve ability to maintain normal platelet counts. Pre- transplant TPO will be given to increase collection of early megarkaryocyte progenitor cells during bone marrow harvest procedures. Assays will be performed to calculate progenitor cell yield and post-transplant time to platelet engraftment will be determined. Both strategies are likely to result in shortening duration of thrombocytopenia, after transplantation. 5) to create an immortalized human megakaryocyte stem cell line either by transfection of a truncated activated mpl plasmid into an early megakaryocyte progenitor cell, or by retroviral infection. 6) to examine leukemia cells for mpl mRNA transcripts as well as their ability to proliferate in response to TPO in order to determine potential clinical situations in which administration would be contraindicated.