Lyn激酶介导FIP1L1-PDGFRA/JAK2信号通路在CEL中的作用及机制研究

固化激活的FIP1L1-PDGFRA酪氨酸激酶（简称F/P）可促嗜酸性粒细胞克隆增殖、异常活化并浸润损害脏器，导致慢性嗜酸性粒细胞白血病（CEL）发生，严重威胁患者生命。前期工作发现，JAK2介导F/P激酶促细胞增殖，抑制凋亡和诱导细胞活化，同时发现Lyn激酶在F/P（+）CEL患者过度磷酸化并可伴随JAK2阻断而被抑制；为深入探讨Lyn激酶介导F/P/JAK2信号在CEL中的作用机制，项目首先明确F/P(+)嗜酸性细胞Lyn与活化的F/P及JAK2的关系；在此基础上，特异阻断Lyn激酶，观察细胞增殖凋亡及移动活性的变化，并检测Lyn作用的下游分子；然后，建立F/(+)CEL小鼠移植模型，观察Lyn激酶抑制后受累靶器官功能及组织病理学变化，阐明Lyn激酶介导F/P/JAK2诱导嗜酸性细胞活化浸润损害脏器的作用机理；为研发F/P(+)CEL及其他原因不明的嗜酸性细胞浸润相关疾病提供干预靶标。

The constructive tyrosine kinase of FIP1L1-PDGFRA promoting eosinophils proliferation, abnormal activation and end-organ infiltration, leads to the occurrence of chronical eosinophils leukemia (CEL). In our previous study, we found JAK2 mediated F/P promoting cell promotion, apoptosis arrest and induce cell degradulation. And the excessive phosphorylation of Lyn in F/P(+) CEL patients was observed and it can be inhibited by blockade of JAK2 expression. To further investigate the role and mechanism of Lyn in the F/P/JAK2 signaling pathway in CEL cell, we first testify the relation of Lyn activity with the activation of F/P and JAK2 in F/P(+) eosinophil cells. Based on these results, we observe inhibition effect of specific Lyn inhibitor or siRNA on the eosinophil cellular proliferation, cellular apoptosis, cellular migration and degradulation and also detect the downstream moleculars of Lyn kinase. And then in the established F/P(+) CEL murine model, we survey the function and pathology of involved end-organs after Lyn inhibition, to clarify the mechanism of Lyn-mediated F/P/JAK2 signal pathway to induce eosinophil cells activation and showing damage on the end-organs. These above results will aid to provide the intervene target for the F/P(+) CEL and other eosinophil-infiltration diseases with unknown reasons.