C-MPL LIGAND IN HEALTH AND DISEASE

该项目有六个主要目标： 1)以确定MPL的生理和病理生理调节 配体（TPO）。 将测定健康志愿者的血清TPO水平， 以及患有多种内科和外科疾病的个体。 这 数据将用于确定TPO的正常生理范围， 在病理状态下，TPO产生的调节信号和 负责TPO生产的器官。 这些结果将 在开发TPO给药的临床策略中很重要。 2)为了确定TPO给药对血小板减少的影响， 患者和血小板置换供体。 这些研究将涉及给予 TPO和测定对血小板动力学和血小板聚集的总体影响 函数， 这将包括以下血小板计数以及 进行出血时间和血小板聚集测定。 3)确定TPO给药对输血医学的影响。 血小板分离供体将接受TPO;因此，血小板分离 血小板产量、受体血小板存活率和血小板功能 将确定接收者。 TPO给药患者 血小板减少症和血小板分离供体可能导致 减少危及生命的血小板减少症的持续时间， 血小板去除术的好处 4)探讨TPO在骨髓移植中的作用。 移植后 将给予TPO，以尝试缩短血小板聚集时间 移植和提高维持正常血小板计数的能力。 预处理 给予移植TPO以增加早期巨核细胞的采集 在骨髓收获过程中获得祖细胞。 测定将 计算祖细胞产量和移植后时间， 将测定血小板植入。 这两种策略都可能 导致移植后血小板减少症持续时间缩短。 5)创造一个永生化的人类巨核细胞干细胞系， 将截短的活化mpl质粒转染到早期 巨核细胞祖细胞，或通过逆转录病毒感染。 6)检测白血病细胞的mpl mRNA转录物以及它们的 增殖能力，以确定潜在的 禁忌给药的临床情况。

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.