生物钟核心基因Bmal1直接转录激活Tal1及其信号通路调控血管内皮细胞功能的研究

Cardio-cerebrovascular diseases are closely related to the circadian clock disorder, and the vascular endothelial dysfunction is the pathological basis of cardio-cerebrovascular diseases. Recently, we have found that the circadian clock gene knockout mice show vascular endothelial dysfunction, and its molecular mechanism remains to be studied. In the preliminary experiments, the enhanced vascular permeability in Bmal1 gene knockout mice was corresponding to down-regulating expression level of S1P and cell junction’s molecules of vascular endothelial cells. It is speculated that the molecular mechanism is to directly transactivate the transcription factor Tal1 and its downstream signaling pathway resulting in regulating the function of vascular endothelial cells by circadian clock gene Bmal1. We want to apply the chromosome immunoprecipitation, siRNA and adenovirus transfection experiments to study endothelial barrier function, vasodilation and angiogenesis as well. Those need to be confirmed that the circadian clock core gene Bmal1 directly regulates Tal1 transcription and its downstream signaling pathway in different models including transgenic mice of Bmal1 or Tal1, primary vascular endothelial cells, DNA and proteins. This study will provide new ideas and pharmaceutical targets for the prevention and treatment of cardio-cerebrovascular diseases.

心脑血管疾病与生物钟紊乱密切相关，血管内皮细胞功能失调是多种心脑血管疾病的病理基础。近年我们的研究发现，生物钟基因敲除小鼠表现血管内皮细胞功能障碍，其分子机制仍然有待研究。在预实验中，生物钟核心基因Bmal1敲除小鼠的血管通透性的增加，与血管内皮细胞表达的连接分子以及S1P分子的水平降低有关。推测其分子机制是通过生物钟基因直接转录激活内皮细胞特异性的转录因子Tal1，及其下游的信号通路，调控血管内皮细胞的功能。我们希望应用染色体免疫共沉淀，siRNA和腺病毒转染，血管的屏障，舒张，生成等实验，在Bmal1和Tal1的转基因小鼠，血管、原代血管内皮细胞，DNA和蛋白质分子等多层次，证实生物钟核心基因Bmal1直接转录调节Tal1，并通过其下游信号通路对内皮细胞介导的血管通透性，血管舒张和血管生成等功能进行调控。此研究将为心脑血管疾病的防治提供新的思路和药物靶点。

心脑血管疾病的发生与发展与生物钟紊乱密切相关，血管内皮功能失调是多种血管病发生和发展的原因之一，但是生物钟紊乱和内皮细胞功能障碍的分子机制还不清楚。我们的初步实验发现，生物钟核心基因Bmal1敲除小鼠的血管通透性的增加，与内皮细胞的转录因子Tal1、血管内皮细胞表达的连接分子以及S1P信号分子的水平降低有关。在进一步应用Bmal1和Tal1的转基因小鼠，动物血管、原代血管内皮细胞，DNA和蛋白质分子等多层次实验，证实生物钟核心基因Bmal1直接转录调节Tal1，阐明其通过下游信号通路对内皮细胞介导的血管通透性，血管舒张和血管生成等功能进行调控。本研究拓展了心脑血管疾病和内皮功能障碍发生机制的认识，为疾病的防治提供新的理论基础及分子靶标。