骨髓增殖性肿瘤（MPN）易伴发心脏损伤，其机制不明。我们既往研究发现JAK2V617F突变的MPN小鼠心肌纤维化增加。JAK2V617F突变主要引起JAK通路持续激活、骨髓干细胞分化异常，而激活JAK通路可增加细胞增殖和分化关键调控因子激活素A（Activin A）的分泌。我们前期实验已观察到激活素A促进心肌纤维化。因此推测，激活素A参与JAK2V617F突变MPN骨髓干细胞向心肌成纤维细胞异常分化的调控。本项目将通过转基因动物模型、干细胞示踪等方法，明确激活素A在 JAK2V617F突变MPN骨髓干细胞分化为成纤维细胞中的调控作用；利用蛋白芯片技术寻找关键的调控分子，并结合CRISPR/Cas9基因编辑等方法干预相关分子的表达，阐明激活素A调控JAK2V617F突变MPN骨髓干细胞异常分化促进心肌纤维化的分子机制，为肿瘤心脏病的研究和有效干预提供新的视野。

Myeloproliferative neoplasms (MPN) are prone to cardiac injury, and the underlying mechanism is unclear. Our previous studies found that myocardial fibrosis increased in MPN mice with JAK2V617F mutation. JAK2V617F mutation leads to consistent activation of JAK signaling pathway andabnormal differentiation of bone marrow stem cells. Activation of JAK pathway can increase the secretion of Activin A, a key regulator of cell proliferation and differentiation. We have observed that activin A leads to myocardial fibrosis in our previous experiments. Therefore, we speculate that activin A is involved in the regulation of abnormal differentiation of bone marrow stem cells from MPN with JAK2V617F mutant into cardiac fibroblasts. In this study, we will clarify the regulatory mechanism of activin A in the differentiation of bone marrow stem cells from MPN with JAK2V617F mutant into fibroblasts through experimental techniques such as transgenic animal models and stem cell tracing. We will also use protein chip technology to find key regulators, and combine CRISPR/Cas9 gene editing and other methods to interfere with the expression of related molecules. This project will elucidate the molecular mechanism of activin A regulating abnormal differentiation of bone marrow stem cells from MPN with JAK2V617F mutant to promote myocardial fibrosis, and provide a new perspective for the research and effective intervention of cancer heart disease.