内皮细胞TRPV4-SKCa3耦联稳态失调在高血压血管功能稳态失调中的作用及机制研究

The applicant is mainly engaged in the research of molecular identity of arterial tension, blood pressure regulation and intervention strategies. We have found (1) Endothelial TRPV4-SKca3 coupling (Hypertension 2013) and endothelia TRPV4-C1 coupling (Arterioscler Thromb Vasc Biol 2010 Nov ;Arterioscler Thromb Vasc Biol 2010 Apr) regulate endothelial homeostasis, including membrane potential, intracellular calcium. (2) Endothelial cGMP negative feedback and calcium homeostasis (Proc Natl Acad Sci USA, 2012). In the present proposal, we plan to (1) examine the effect and molecular mechanisms of disrupting endothelial TRPV4-SKca3 coupling under hypertension; (2) examine the protective effect of api for TRPV4-SKca3 coupling.

内皮细胞通过蛋白质分子间空间、功能耦联有效地调控血管稳态。申请人从事血管稳态调控研究，以第一/通讯作者发现（1）内皮细胞TRPV4-SKCa3耦联（Hypertension 2013）、TRPV4-C1耦联（Arterioscler Thromb Vasc Biol 2010 Apr；Arterioscler Thromb Vasc Biol 2010 Nov）（2）细胞cGMP调控钙稳态机制（Proc Natl Acad Sci USA 2012）（3）筛选出小分子靶向激活TRPV4-SKca3（Br J Pharm 2012；FEBS J 2012）。在此基础上，拟开展研究（1）代表性病理条件（高血压）内皮细胞TRPV4-SKca3耦联稳态失调的分子机制；（2）TRPV4-SKca3耦联稳态失调的干预策略。课题的开展有助于从内皮细胞角度阐明血管功能稳态的关键信号通路、网络模式及保护策略

内皮细胞通过蛋白质分子间的空间、功能耦联有效地调控血管稳态。申请人从事血管稳态调控研究，本课题发现（1）代表性病理条件下（高血压）内皮细胞TRPV4-SKca3耦联稳态失调的分子机制；（2）TRPV4-SKca3耦联稳态失调的干预策略，发现靶向药物先导分子JNc440。课题的开展有助于从血管内皮细胞角度阐明血管功能稳态的关键信号通路、网络模式及保护策略（EMBO Mol Med. 2017 Nov;9(11):1491-1503（with Cover Story, “A bridging approach against hypertension”）；Hypertension. 2017 Nov 6./HYPERTENSIONAHA.117.09767，with Editorial Commentary）。