MicroRNA let7-b and long non-coding RNAs in endothelial regeneration during atherosclerosis

动脉粥样硬化是一种脂质驱动的炎症性疾病，主要发生在动脉分支点，是心肌梗死和中风的病因。这些偏好部位的血流紊乱会诱导内皮细胞（EC）功能障碍，并通过microrna介导的Notch1信号的抑制来限制高脂血症应激时内皮细胞的再生。然而，调控动脉内皮细胞再生能力的分子机制目前尚不完全清楚。我们的初步结果表明，在内皮细胞中，miRNA-let-7b的表达减少可以防止内皮细胞凋亡，促进内皮细胞增殖，并可能通过靶向一个或多个长链非编码rna （lncRNAs）来促进Wnt和Notch1信号传导。因此，我假设let7b抑制lncrna通过调节Wnt和Notch1信号通路的串扰，损害了动脉粥样硬化期间功能失调的ECs的再生。为了验证这一假设，我将评估let-7b/lncRNA相互作用对小鼠动脉粥样硬化期间内皮功能和内皮再生的影响，并研究这些相互作用是否通过减少Wnt/Notch轴的激活而损害内皮再生并增强动脉粥样硬化病变的形成。此外，我将研究let-7b在调节人类ECs中Wnt和Notch1通路成员基因表达中的作用。我期望在动脉粥样硬化期间发现一种新的内皮再生机制，其特征是lncRNA诱导的信号通路的激活，如Wnt和Notch，这对ECs的动脉规范很重要。因此，靶向内皮let-7b-lncRNA相互作用可能为改善内皮健康和减少动脉粥样硬化提供一种新的治疗策略。

Atherosclerosis is a lipid-driven inflammatory disease that mainly develops at branching points of arteries and causes of myocardial infarction and stroke. Disturbed flow at these predilection sites induces endothelial cell (EC) dysfunction and limits endothelial regeneration upon hyperlipidemic stress by microRNA-mediated inhibition of Notch1 signaling. However, the molecular mechanisms regulating the regenerative capacity of arterial ECs are currently incompletely understood. Our preliminary results indicate that reduced expression of miRNA-let-7b in ECs protects against endothelial apoptosis, improves endothelial proliferation, and promotes Wnt and Notch1 signaling probably by targeting one or multiple long non-coding RNAs (lncRNAs). Therefore, I hypothesize that suppression of lncRNAs by let7b impairs regeneration of dysfunctional ECs during atherosclerosis by regulating the crosstalk of Wnt and Notch1 signaling pathways. To test this hypothesis, I will assess the effects of let-7b/lncRNA interactions on endothelial function and endothelial regeneration during atherosclerosis in mice and study whether these interactions impair endothelial regeneration and enhance atherosclerotic lesion formation by reduced activation of the Wnt/Notch axis. Moreover, I will investigate role of let-7b on regulating gene expression of Wnt and Notch1 pathway members in human ECs. I expect to identify a novel mechanism of endothelial regeneration during atherosclerosis characterized by the lncRNA induced activation of signaling pathways, such as Wnt and Notch, which are important for the arterial specification of ECs. Thus, targeting endothelial let-7b-lncRNA interactions may provide a new therapeutic strategy to improve endothelial health and decrease atherosclerosis.