Mechanosensation in vascular endothelium: the role of purinergic signalling

血管内皮的机械感觉：嘌呤能信号的作用

• 批准号: 2241022
• 金额: --
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2241022
• 关键词: Mechanosensation; vascular; endothelium; role; purinergic

The lumen of arteries is lined by a monolayer of endothelium which is in direct contact with the shearing mechanical force of blood flow. The endothelium needs to sense and respond to changes in such forces (blood flow) and release signalling molecules that alter vascular tone, modulating local tissue perfusion and systemic blood pressure. The molecular basis for shear force detection in endothelium is poorly defined yet may represent an important drug target for the modulation of blood pressure and vascular remodeling following ischemia. ATP can be physiologically released by mammalian cells following mild mechanical stimulation, though the cellular release routes remain controversial. The biological effects of extracellular ATP are mediated by activation purinergic receptors (P2Y, metabotropic; P2X ionotropic). This project will investigate the molecular mechanisms underlying flow-dependent ATP release in vascular endothelium and the subsequent pathways through which purinergic receptors signal to produce vasodilatory molecules and influence vascular tone. The project will involve training in cutting-edge techniques in vascular biology and pharmacology including pressure myography, calcium imaging, lentivirus production and delivery, cellular bioimaging conditions of flow and work with human tissue.

动脉的管腔由一层内皮细胞排列，内皮细胞与血流的剪切机械力直接接触。内皮细胞需要感知和响应这种力量（血流）的变化，并释放信号分子，改变血管张力，调节局部组织灌注和全身血压。内皮细胞剪切力检测的分子基础尚不明确，但可能是缺血后调节血压和血管重构的重要药物靶点。哺乳动物细胞在轻微的机械刺激下可以生理释放ATP，尽管细胞释放途径仍然存在争议。细胞外ATP的生物学效应是通过激活嘌呤能受体（P2Y，代谢性；P2X离子性）介导的。本项目将研究血管内皮中流动依赖性ATP释放的分子机制，以及嘌呤能受体信号产生血管舒张分子和影响血管张力的后续途径。该项目将涉及血管生物学和药理学的尖端技术培训，包括压力肌图、钙成像、慢病毒的产生和传递、细胞生物成像条件的流动和与人体组织的工作。