ERK/MAPK信号通路通过TCF21调控血管平滑肌细胞分化在Loeys-Dietz综合征动脉病变中的作用及机制研究

Loeys-Dietz综合征（LDS）是一种常染色体显性遗传性结缔组织病，以快速进展的主动脉瘤/夹层为主要特征。目前，LDS的发病机制不清楚，缺乏明确的干预靶点及有效的治疗药物。前期研究中，我们在国际上首次建立了LDS患者特异性诱导多能干细胞（iPSC）疾病模型。运用该模型，我们发现TGFBR突变导致ERK1/2磷酸化水平持续降低，血管平滑肌细胞（VSMC）分化受限，功能减退；同时，外显子测序发现抑制VSMC分化的转录因子TCF21表达显著升高。据此假设：ERK1/2磷酸化水平下降可能通过上调TCF21从而抑制VSMC分化，激活ERK信号通路可以抑制TCF21从而促进VSMC分化。为了验证这一假说，我们将研究LDS患者特异性iPSC疾病模型中ERK信号通路对TCF21表达的调控以及TCF21抑制VSMC分化的作用及机制。本研究将为阐明LDS的发病机制及寻找有效的干预靶点提供重要的理论依据。

Loeys Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by a rapidly progressing aortic aneurysm and (or) dissection. However, litter is known about the undrling pathogenesis, and there is no clear intervention target and effective medical treatment. In the previous study, we established the LDS patient specific iPSC disease model for the first time in the world. Using this model, we found that TGFBR mutation caused the phosphorylation of ERK1/2 phosphorylation to decreas, VSMC differentiation to be limited, and function to decline; meanwhile, exon sequencing found that the expression of TCF21, a transcription factor that inhibited VSMC differentiation, increased significantly. Therefore, we hypothesized that the decrease of ERK1/2 phosphorylation might inhibit VSMC differentiation by up regulating TCF21, and activating ERK signaling pathway could inhibit TCF21 and promote VSMC differentiation. In order to test this hypothesis, we will study the regulation of ERK signaling pathway on TCF21 expression and the effect and mechanism of TCF21 on VSMC differentiation. This study will provide an important theoretical basis for clarifying the pathogenesis of LDS and finding effective intervention targets.