Cav1.2钙离子通道功能受到选择性剪接这一重要的转录后调节机制的精细调控，我们过去的研究发现这种调节机制的紊乱参与了多种心血管疾病的发生发展。最近，我们发现高血压动脉中剪接调控因子PTBP1的表达降低，同时Cav1.2钙通道剪接外显子exon 8/8a表达紊乱。PTBP1可以直接调控血管平滑肌Cav1.2剪接外显子exon 8/8a的表达。而且，PTBP1敲降后Cav1.2对钙拮抗剂敏感性明显降低。所以，我们推断PTBP1蛋白通过调控剪接事件参与了高血压血管中Cav1.2钙通道的功能调节。为此，我们提出3个研究目标：1）阐明高血压血管中exon 8/8a与PTBP1的表达水平及其相关性；2）阐明PTBP1对Cav1.2电生理特征、血管肌张力和对钙通道拮抗剂的敏感性的影响及机制；3）探究在体操控血管平滑肌内PTBP1表达能否影响动脉血压？这一项目的开展能为高血压的治疗提供一个崭新的策略。

The function of Cav1.2 calcium channel is optimized by alternative splicing, one of most important post-transcriptional modulation mechanisms, our previous studies indicated that its dysfunction is involved in the genesis and development of several cardiovascular diseases. Recently, we found that the splicing factor PTBP1 was downregulated and Cav1.2 alternative exon 8/8a was also dysregulated in the hypertensive arteries. PTBP1 could directly switch the Cav1.2 alternative exon 8/8a. Moreover, knockdown of PTBP1 desensitized the effects of dihydropyridine on Cav1.2 calcium channel in vascular smooth muscle cells. Therefore, we presume that PTBP1 may make some important roles in the development of hypertension by regulating the Cav1.2 alternative splicing. Thus, we propose 3 specific aims: 1) to elucidate the expressions of exon 8/8a and PTBP1 and their relationship in hypertensive arteries; 2) to study the effects and underlying mechanisms of PTBP1 on the modulation of the Cav1.2 electrophysiological function, vascular myogenic tone and dihydropyridine sensitivity; and 3) to explore whether in-vivo manipulation of PTBP1 will affect the arterial blood pressure. This project will provide a newly potential approach to the management of hypertension.