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

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.

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。

大血管狭窄是导致心血管疾病的一个主要的原因，其发生的细胞和遗传机制很大程度上是未知的，部分原因是在于其胚胎生长期复杂的结构和转化过程受到干预。对大血管生成调控的研究有助于阐明大血管狭窄的病因，并为大血管损伤后的修复提供治疗依据。基于前期研究，我们推测STATs介导的I型干扰素炎性微环境症信号在大血管狭窄发生发展中发挥了重要的调控作用，而HDAC3是关键的表观调控因子。因此，本项目研究包括对于炎性微环境诱导的HDAC3在大血管内皮前体细胞EPCs调控的下游信号途径，以及炎性信号对大血管EPCs的调控规律中关键问题的阐明，深入理解大血管狭窄的病因，为大血管狭窄修复的再生性治疗提供靶点和依据。本项目的研究阐明了IFN-α/β调控的免疫系统在生理及炎症状态对大血管生成的调控作用；揭示了在大血管生成过程中IFN-α/β信号激活对于天然免疫细胞和炎症因子的稳态功能调控作用；明确了大血管EPCs的分化、增殖和迁移受激活的天然免疫细胞的作用调控；揭示了HDAC3介导的 I型IFNs对于大血管EPCs的信号调控网络及并完成小分子抑制剂的筛选。研究成果包括在2020年发表Sci Adv论文1篇，研究过程中培养3名博士毕业。