C-MPL LIGAND IN HEALTH AND DISEASE

这个项目有六个主要目标： 1)确定MPL的生理和病理生理调节 配体(TPO)。健康志愿者的血清TPO水平将测定为 以及患有多种内科和外科疾病的个人。这 数据将被用来确定TPO的正常生理范围， 病理状态的范围，TPO产生的调节信号和 负责TPO生产的机关(S)。这些结果将是 在制定TPO给药的临床策略方面很重要。 2)测定TPO给药对血小板减少的影响 患者和血小板移植供者。这些研究将涉及到给予 TPO及其对血小板动力学和血小板整体影响的测定 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性测定。 3)了解TPO给药对输液用药的影响。 血小板移植供者将接受TPO；因此，血小板移植 受者的血小板产量、存活率和血小板功能 将确定收件人。TPO对慢性阻塞性肺疾病患者的治疗 血小板减少症和血小板减少性捐献者很可能导致 减少危及生命的血小板减少的持续时间并增加 血小板移植的好处。 4)评价TPO在骨髓移植中的作用。移植后 将给予TPO，试图缩短血小板形成的时间 植入并提高维持正常血小板计数的能力。Pre- 移植的TPO将用于增加早期巨核细胞的收集 骨髓采集过程中的祖细胞。化验结果将是 执行以计算祖细胞产量和移植后时间以 血小板的植入将被确定。这两种战略都可能 导致移植后血小板减少的持续时间缩短。 5)建立永生化的人类巨核细胞干细胞系 截短型活化MPL表达载体的早期表达 巨核系祖细胞，或通过逆转录病毒感染。 6)检测白血病细胞的MPL mRNA转录本及其 对TPO作出反应的增殖能力，以确定潜力 禁止给药的临床情况。

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.