炎性微环境下HDAC3调控内皮祖细胞修复大血管狭窄的机制研究

大血管狭窄是导致大血管疾病的主要原因，部分诱因在于大血管内皮祖细胞（endothelial progenitor cells, EPCs）生成不足。我们发现EPCs来自生心区细胞亚群（Nature 2011），并首次确证了炎症信号在大血管EPCs生成及疾病中的关键作用(Nat Commun 2017)。然而，参与大血管EPCs生成的炎性细胞和信号途径还不清楚。本项目拟探讨炎性微环境下HDAC3表观调控EPCs修复大血管狭窄的机制。采用转基因和突变动物及体外炎性微环境模型等，结合我们在炎性微环境中免疫细胞及表观调控的研究基础（Leukemia 2017、2015, Blood 2014），阐明微环境免疫细胞与大血管EPCs的交互作用规律，揭示HDAC3对于大血管EPCs增殖分化的表观信号调控网络，并进行小分子抑制剂筛选。为深入理解大血管狭窄的病因及修复的再生性治疗提供理论依据和诊疗靶点。

Great vessel stenosis is the major cause of great vessel disease, partially due to insufficient production of great vessel endothelial progenitor cells (EPCs). We found that EPCs were derived from a heart field cell subpopulation (Nature 2011) and for the first time confirmed the critical role of inflammatory signaling in EPCs formation and disease of great vessel (Nat Commun, 2017). However, the inflammatory cells and signaling pathways involved in the formation of great vessel EPCs are still unknown. This project aims to investigate the mechanism of HDAC3 epigenetic regulation of EPCs and the repair of great vessel stenosis in inflammatory microenvironment. The transgenic and mutation animal models and in vitro inflammatory microenvironmental models are employed in the study. Based on our previous progress in immune cells and epigenetic regulation of inflammatory microenvironment (Leukemia 2017, 2015, 2014 Blood), we try to clarify the mechanisms of interaction between microenvironmental immune cells and great vessel EPCs. We also propose to reveal the HDAC3 epigenetic signal regulatory networks of the proliferation and differentiation of EPCs, and discover small molecule inhibitors of HDAC3. This work may provide the basis for understanding the etiology of great vessel stenosis and the strategy of regenerative therapy.