PAK1调控GATA1的降解在原发性骨髓纤维化中的作用和机制研究

原发性骨髓纤维化（PMF）是骨髓增殖性肿瘤（MPN）中预后最差的类型，严重影响患者生活质量，重者危及生命。巨核细胞异常累积是诱导PMF发病的重要因素，诱导异常巨核细胞分化是潜在的治疗PMF的新途径。然而，由于PMF巨核细胞异常分化机制不清，严重制约其靶向干预治疗的探索。有研究显示，GATA1是调控造血干细胞向巨核-红系细胞分化的关键转录因子，但在PMF巨核细胞中缺失。我们前期研究发现，PAK1是调控GATA1降解的关键激酶，在PMF细胞中过度活化，故推测：PAK1是调控PMF巨核细胞中GATA1缺失的重要激酶，参与调节PMF的发生发展。为此，本课题拟建立小鼠巨核细胞中敲除PAK1基因的PMF模型，从细胞和在体水平，明确PAK1调控GATA1的位点、及其调控PMF巨核细胞GATA1表达的分子机制。如获成功，可为从翻译后调控解析PMF发生发展提供可靠的实验依据。

Primary myelofibrosis(PMF), as one type of myeloproliferative tumor (MPN), has the worst prognosis, which seriously affects the quality of life of patients, even has life-threatening risk. The abnormal accumulation of megakaryocytes directly promote the progress of PMF, and induction of megakaryocytic differentiation is considered to be a novel strategy to therapy PMF. However, the unclear mechanism in megakaryocytic differentiation seriously restricts to explore new strategy for targeting treatment of PMF. As the report, GATA1 plays an important role during the differentiation of hematopoietic stem cells to megakaryocyte-erythroid cells, but is founded lost expression in PMF megakaryocyte. In our previous study, we found that PAK1 was activated in PMF cells, and was a pivotal kinase for regulation of GATA1 degradation. Here, we further speculate that PAK1 directly induces GATA1 lost expression in PMF megakaryocyte, and contributes to the development of PMF. Next, we plan to verify the regulatory site of GATA1 by PAK1, and explore the molecule mechanism that PAK1 regulates GATA1 expression by PAK1-/- PMF mouse model in vitro and in vivo. Once successfully, this project can provide conclusive results for explanation of PMF occurrence and development from post-translation level.