重症脓毒症导致胸腺萎缩,是造成适应性免疫缺陷的重要因素。在前期国自然支持下，申请人从“应急造血”角度阐述了重症脓毒症导致胸腺萎缩的分子机制，并且发现脓毒症模型小鼠胸腺在萎缩后可发生“反跳性增生”这一重要现象。根据前期结果，申请人提出：胸腺反跳性增生需要同时具备两个条件： 1）造血干、祖细胞内部抑制T淋巴细胞生成的因素被解除；2）胸腺造血微环境中促进T淋巴细胞生成的因素增强。申请人拟采用脓毒症模型小鼠，探讨骨髓和胸腺中造血干、祖细胞数目与胸腺增生的关系；采用表达谱系分析、体外OP9-DL1细胞共培养、体内竞争性干、祖细胞移植等方法，从造血干、祖细胞定向分化和迁移能力角度探讨导致胸腺萎缩的因素是否解除；从IL-7、IL-22促进胸腺细胞发育的信号通路入手，探讨胸腺微环境中促进胸腺细胞分化发育的因素，从应急造血角度阐明胸腺反跳性增生的机制，为寻找促进脓毒症患者免疫功能恢复的治疗方法提供新思路。

Severe sepsis could induce thymic atrophy, and subsequently lead to a decrease of T lymphocytes and secondary adaptive immune deficiency. Supported by National Natural Science Foundation, we have explored the molecular mechanisms involved in severe sepsis-induced thymic atrophy. Strikingly, we observed a rebound thymic hyperplasia in septic mice models. According to the preliminary results, we hypothesized that there are two important aspects of factors may be involved in thymic hyperplasia: 1) intrinsic negative factors in hematopoietic stem/progenitor cells must be relieved; 2) existence of positive factor in thymic microenvironment to promote thymocyte development. To test this hypothesis, we intend to use mouse model of sepsis to investigate kinetic changes in the numbers and function of hematopoietic stem cells and lymphoid progenitor cells; to explore the intrinsic negative regulators for lymphoid commitment, differentiation and migration of bone marrow hematopoietic stem cells and lymphoid cells by using gene expression profiling analysis, in vitro OP9-DL1 cells co-culture and in vivo competitive hematopoietic reconstruction; to investigate the changes in the thymic microenvironment that promote thymocyte development by assessing IL-7, IL-22 levels and their downstream signaling pathways. We expect to clarify the mechanism of "rebound thymic hyperplasia" after sepsis from the view of emergency hematopoiesis.