Piezo1 proteins: Integration of mechanotransduction in microvascular blood flow regulation.

背景技术背景：我们基础血管研究计划的长期目标是了解控制血液如何在休息和运动期间输送到我们的肌肉细胞的机制。最近，科学家们发现了一种存在于哺乳动物血管中的蛋白质（例如，人类和小鼠）称为Piezo1。这种蛋白质具有感知血压和血流的独特能力。我们有兴趣发现Piezo1蛋白如何与其他血管控制系统协调，将血液输送到我们的肌肉。由于男性和女性已被证明调节血压和血流量不同，我们将研究两性中的Piezo1蛋白。* 突变体：1）产生血管中缺乏Piezo 1蛋白的遗传修饰的雄性和雌性小鼠的群体并进行基因分型。2)在基线条件下系统地确定Piezo1通道的血流动力学作用。3)系统地确定Piezo1通道如何与其他血管控制系统相互作用，以及静息和收缩时的血流分布。* 方法：我们开发了一种直接观察活小鼠骨骼肌血管的方法（使用显微镜）。我们将拍摄这些血管和红细胞在各级微血管网络，在休息条件下，并与药物和实验方法，收缩和放松血管的视频。收集的数据将在网络血压和流量的背景下分析血管反应。 * 影响：本提案中实验的综合性质将为未来的科学家提供严格，高质量的培训。我们将首先研究和描述血管中的流量和压力如何“调整”到血管调节，以及2）这种整合如何优化几何形状和布局不同的网络中的血流。*****

BACKGROUND: The long-term objective of our basic vascular research program is to understand the mechanisms controlling how blood is delivered to our muscle cells at rest and during exercise. Recently, scientists have discovered a protein that exists in the blood vessels of mammals (e.g., humans and mice) called Piezo1. This protein has the unique ability to sense blood pressure and blood flow. We are interested in discovering how Piezo1 proteins coordinate with other vascular control systems to deliver blood to our muscles. Since males and females have been shown to regulate blood pressure and blood flow differently, we will study Piezo1 proteins in both sexes. ***OBJECTIVES: 1) Generate and genotype a colony of genetically modified male and female mice which lack Piezo1 proteins in their blood vessels. 2) Systematically determine the hemodynamic roles of Piezo1 channels under baseline conditions. 3) Systematically determine how Piezo1 channels interact with other vascular control systems and blood flow distribution at rest and during contraction. ***APPROACH: We have developed a means to directly observe the skeletal muscle blood vessels in live mice (using a microscope). We will take videos of these blood vessels and red blood cells at all levels of microvascular networks, under resting conditions, and with drugs and experimental methods that constrict and relax vessels. The data collected will be analyzed for vascular responses in the context of network blood pressure and flow. ***IMPACT: The integrated nature of experiments in this proposal will provide rigorous, high-quality training for future scientists. We will be first to 1) investigate and describe how flow and pressure in blood vessels are “tuned” to vascular regulation, and 2) how this integration optimizes blood flow in networks that vary in geometry and layout. *****