染色质重塑复合物INO80调控血管平滑肌细胞表型转化预防血管术后再狭窄的作用和机制研究

血管平滑肌细胞（VSMCs）表型转化是血管术后再狭窄的主要病理基础。以往研究多聚焦于外源性细胞因子和信号通路在VSMCs表型转化中的作用，但染色质结构如何被调节以控制该过程的机制却尚未阐明。我们发现染色质重塑复合物INO80在颈动脉斑块中特异性表达，敲低其关键亚基可促进调控VSMCs表型转化的相关蛋白（KLF4、H2A.Z、THOC2）及VSMCs标志性基因（MYH11、TAGLN）表达异常。据此推测，INO80在VSMCs表型调控中发挥着重要作用，并可能成为预防再狭窄的靶点。为验证此假说，拟首先借助微流控技术和传统细胞实验双重验证INO80对VSMCs迁移、增殖和细胞表型的作用；然后通过生物信息学分析构建INO80调控上述过程的分子网络；最后通过动物实验探讨调控INO80抑制内膜增生的可能。本研究将帮助我们深入理解染色质调控在血管稳态中的作用，开拓血管术后再狭窄预防与治疗的新思路。

Phenotypic switching of vascular smooth muscle cells (VSMCs) is the main pathological process of postoperative restenosis. Previous studies have focused on the role of exogenous cytokines and signaling pathways in phenotypic switching of VSMCs, but how chromatin structure is regulated to control the expression of specific genes in that process has not been clarified. We found that INO80 chromatin remodeling complex and its key subunit, was specifically expressed in carotid artery plaques. Knockdown of INO80 subunit can promote the transcription regulation related to phenotypic switching of VSMCs and the abnormal expression of genomic stable proteins (KLF4, H2A.Z, THOC2) and VSMCs signature genes (MYH11, TAGLN). It is speculated that INO80 plays an important role in phenotypic regulation of VSMCs and may be a target for restenosis prevention. In order to verify this hypothesis, it is proposed to double verify the effects of INO80 on VSMCs migration, proliferation and cell phenotype marker genes in vitro with the tool of microfluidic technology and traditional cell model, and further clarify the mechanism through genomics method. Then, the genomic data of INO80 and other key factors in the restenosis gene expression profile were integrated to construct and verify the molecular network that INO80 regulates that process. Finally, the possibility of inhibiting intimal hyperplasia by regulating this subunit was explored in a living animal model. This study will provide insights into how chromatin factors coordinate with other factors to regulate vascular homeostasis and remodeling, and will offer novel ideas for the prevention and treatment of postoperative restenosis.