磷酸酶SHP-2调节巨噬细胞活化介导炎症性肠病的生理学意义及分子机制研究

The pathology of inflammatory bowel disease (IBD) remains largely unclear. Abnormality in immune responsiveness, including macrophage activation, plays an important role in IBD. It has been reported that alternatively activated macrophages (M2) have a protective role in experimental colitis, while the mechanism underlying requires further investigation. Our previous studies have established a cellular model to record classical-activation of macrophage (M1) in vitro, and found that SHP-2 has a positive regulation on M1 and negative regulation on M2.Then we have generated a macrophage specific SHP-2 knockout mouse line, which is good animal model to study the role of SHP-2 in macrophages in vivo and the progress of dioetyl sodium sulfosuccinate-induced acute ulcerative colitis (UC). Combining with these, we will explore the SHP2-associated molecular mechanism in macrophage activation and the pathology of UC, which might provide better understanding of UC mechanisms and novel treatments for patients.

炎症性肠病（IBD）的发病机制尚未完全明确，肠道粘膜免疫系统功能紊乱在IBD发生发展中扮演重要角色，巨噬细胞介导的固有免疫失调可能是引起IBD的直接原因，已有研究表明旁路激活的巨噬细胞（M2）在实验性肠炎中起保护作用，但其具体机制并不清楚。我们通过预实验在体外建立经典活化巨噬细胞（M1）模型，筛选出磷酸酶SHP-2抑制剂PHPS1参与M1信号通路，SHP-2正向调控M1，进而发现SHP-2负向调控M2。基于以上认识，我们构建巨噬细胞SHP-2敲除小鼠模型，通过丁二酸二辛酯磺酸钠(DSS)诱导急性UC模型，明确SHP-2缺失诱导巨噬细胞活化对UC的免疫调控及分子机制研究，并通过体外培养原代巨噬细胞和细胞株探讨巨噬细胞活化相关信号通路，结合临床UC病人样本分析，充分了解UC的发病机制并为新药开发、个体化的基因诊疗提供研究基础。

溃疡性结肠炎（UC）是肠道粘膜免疫系统功能紊乱引发的疾病，肠道巨噬细胞固有免疫功能失调，由此引发的肠道炎症反应可能是导致UC的直接原因。我们在体外建立了巨噬细胞经典活化（M1）模型，筛选出炎性调控蛋白SHP-2抑制剂PHPS1正向调控M1，进而发现SHP-2负向调控巨噬细胞旁路活化通路（M2）。为进一步研究SHP-2与UC的关系，我们成功构建髓系细胞条件性敲除SHP-2（SHP-2 KO）小鼠，用丁二酸二辛脂磺酸钠喂予小鼠诱导急性肠炎模型。与野生（WT）小鼠相比，髓系细胞SHP-2 KO小鼠肠炎更严重。本课题充分说明磷酸酶SHP-2通过调控巨噬细胞功能介导UC发生发展，这些研究结果为充分了解UC发病机制、新药开发和个体化基因诊疗提供理论依据。