骨髓微环境免疫失衡是急性髓性白血病(AML)难治和死亡重要原因。新近证明，骨髓交感神经组织对骨髓造血和免疫功能具有重要调控作用。我们前期发现，AML骨髓中存在交感神经组织病变及辅助性T(Th)细胞免疫网络失衡，且二者显著相关。本项目拟在系统生物学框架内，采用网络分析方法，并结合实验验证，构建AML骨髓局部交感神经组织以及骨髓区域微环境Th细胞的贝叶斯网络模型，明确其关键节点；通过体外骨髓神经细胞与BMDCs、CD4+T、AML细胞共培养，研究其下游相关通路，揭示骨髓神经对Th免疫网络调控作用，及其对AML细胞生物学行为的作用及机制。构建骨髓神经功能缺失（及正常）AML小鼠，体内监测小鼠AML发生发展中神经损伤与Th免疫网络关系，应用神经递质及保护剂，观察对小鼠骨髓中Th免疫网络失衡的逆转作用，以期揭示从AML骨髓局部交感神经组织损伤到AML发生发展的内在网络机制，为AML靶向治疗提供借鉴。

Immunological deregulation in bone marrow microenvironment is the main reason for refractoriness and death of patients with acute myeloid leukemia (AML). Bone marrow sympathetic nerve tissue has been proven to be vital in regulating the hematopoiesis and immunology in bone marrow microenvironment. Our previous study has confirmed the sympathetic neuropathy and imbalanced Th immunological network in bone marrow of AML patients, and they are correlated significantly. Under the framework of systems biology and using experiments, we will construct the Bayesian network of bone marrow sympathetic nerve tissue and Th subsets variation of AML and clarify the key cells and molecules. After co-culturing bone marrow nerve cells with BMDCs, CD4+ T cells or AML cells, we will investigate the bone marrow sympathetic nerve regulatory mechanism on Th immunological network, and clarify their effects on biological behavior of AML cells. We will illuminate the detailed mechanism of nerve/Th network in AML development after studying the related signaling pathway. Furthermore, we will establish AML mouse model with or without BM nerve functional deficiency and monitor the sympathetic neuropathy and Th immunological network in vivo. We will study the effects and mechanisms on reversing imbalanced Th immunological network after applying neurotransmitter and nerve protection. Our project will demonstrate the detailed mechanisms during the process from BM sympathetic nerve damage to the development of AML, and provide strategy for AML targeting therapy.