5-HT是调控thrombopoietin合成的调节子？

血小板生成素TPO生成调控是尚未解决的科学问题。目前认为肝肾产生TPO基本恒定，骨髓产生TPO可调节，但机制不清楚。我们基于对5-HT在调控巨核细胞系造血的原创性工作（Stem Cells，2007；2014）提出出血应激时血小板激活释出5-HT，作用于骨髓基质细胞（MSCs）5-HT2型受体，激活Erk1/2通路，在转录水平调控TPO生成之假说。本研究将验证：（1）MSCs表达5-HT2型受体，5-HT通过5-HT2型受体对MSCs发挥作用；（2）5-HT激活5-HT2受体和Erk1/2通路，在转录水平调节TPO合成；（3）5-HT促进微粒（MPs）释放和增加MPs中TPO含量。上述目标完成后，制作5-HTR2b Knock-out小鼠模型，进一步验证体外结果。本研究将证明血小板源性5-HT是否是TPO合成的调节子，为解答如何调控TPO的生成和指导临床使用TPO有重要的科学意义。

Thrombopoietin (TPO) is a major cytokine for megakaryopoiesis and platelet production. It is synthesized by liver, kidney and bone marrow stromal cells. However, how to regulate TPO production is still unclear. At present, it was found that liver and kidneys produce TPO consistently. And a proportion of total TPO is produced by stromal cells in the bone marrow and their TPO mRNA production is sensitive to factors produced by platelets and thus also linked to platelet number.   The mechanism of action remains unknown. Since serotonin (5-HT) can be released from the active platelets when the body undergoing bleeding or stress, it may functions as an essential hormonal mediator regulating TPO production...Here, we hypothesized that 5-HT exerts its effect through the binding of 5-HT 2 receptors, regulating TPO production in bone marrowl stromal cells (MSCs). In this study, we will test our hypothesis though three objectives:(1)To identify the expression of 5-HT2 receptors on MSCs of bone marrow;（2） To determine the role of 5-HT2 receptors and Erk1/2 signaling on TPO released from MSCs at mRNA and protein levels; (3)To investigate the impact of 5-HT on the production of TPO mRNA and protein contained within the MSCs –derived microparticles (MPs). Furthermore, the relationship between the plasma levels of 5-HT and TPO, and the expression of MSCs TPO mRNA of bone marrow in 5-HTR2b Knock-out mouse model will be studied...Results from this study may show that 5-HT stimulates TPO production from MSCs in both dissociative and MP-bounded form, which will help us to understand the physiological regulation of TPO production.