骨髓血管内皮细胞HIF-1α低表达介导的自噬受损在allo-HSCT后aGVHD中的作用及机制研究

急性移植物抗宿主病(aGVHD)是异基因造血干细胞移植后常见且严重的并发症，是亟待解决的重要科学问题。低氧诱导因子-1α(HIF-1α)作为调控血管内皮细胞活性氧的关键分子，与自噬密切相关。近年来，申请人围绕aGVHD的发病机制开展了系列研究，发现：aGVHD患者骨髓血管内皮细胞的HIF-1α及自噬水平低于非GVHD患者；aGVHD患者骨髓血管内皮细胞和造血干细胞数量和功能受损；骨髓血管内皮细胞自噬缺陷/不足是其功能受损，进而支持造血减弱的关键因素。所以我们提出假设，HIF-1α低表达介导的自噬缺陷/不足所致骨髓血管内皮细胞损伤是造血干细胞异常，造血、免疫重建延迟，炎症反应激活，进而导致aGVHD发生和发展的重要原因。本课题将从血管内皮细胞自噬这一崭新视角，通过前瞻性临床研究、体内、外实验，系统阐述HIF-1α依赖的自噬对aGVHD骨髓血管内皮细胞与造血干细胞损伤与修复作用及其调控机制。

Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and its pathogenesis has not been fully elucidated. Hypoxia-inducible factor-1 alpha (HIF-1α) plays an essential role in assisting endothelial cells to adapt to hypoxic environments, via regulating autophagy. Our series of reports showed that: 1) upregulated HIF-1α and defective autophagy were found in bone marrow endothelial cells from aGVHD patients compared to matched patients without aGVHD; 2) reduced and dysfunctional bone marrow endothelial cells and hematopoietic stem cells were found in aGVHD patients compared with those without aGVHD, with elevated intracellular reactive oxygen species levels; 3) the autophagy in endothelial cells could modulate their ability of supporting hematopoiesis. Therefore, we postulate that down-regulated HIF-1α-dependent autophagy may conduct the impairment of bone marrow endothelial cells, which would weaken their ability to support hematopoietic and immunologic reconstitution, and lead to an active inflammatory process to aggravate aGVHD. This work would demonstrate the role of HIF-1α-dependent autophagy of endothelial cells in the pathogenesis of aGVHD in vitro and in vivo, thus providing a promising therapeutic target for aGVHD patients in the future.