Piezo mechanosensitive receptor interplay with tight junction proteins for maintenance of epithelial cell number and integrity

考虑到压电蛋白作为机械感受器，在生理细胞挤出和分裂中起着至关重要的作用，我们项目的目的是将这些发现转化为哺乳动物，并提供它们与细胞骨架和紧密连接蛋白相互作用的机制描述。然后，我们将利用小鼠实验模型，研究依赖于压电检测的机械力在体内肠上皮细胞周转中发挥作用的分子机制。基于这一假设，本课题的具体科学目标如下：1.描述Piezo1在体内肠上皮更新中的作用。2.确定Piezo1与细胞脱落的相关性，作为避免上皮细胞数量积累的过程。3.确定Piezo1与细胞分裂的相关性，作为补充肠上皮的过程。4.表征生理条件下人类和小鼠肠道中的压电调节分子途径，特别关注细胞骨架和TJ。我们将有助于对最近发现的能够感知机械力的分子（Piezo1）的功能以及介导信号传递到细胞骨架和TJ蛋白的下游途径的机制知识总之，我们的项目将提供关于机械力感觉和细胞间连接作为肠道上皮细胞周转调节剂的创新知识，在体内平衡和病理学方面。

Considering Piezo proteins as mechanoreceptors with a crucial role in physiological cell extrusion and division, the aim of our project will be to translate these findings into mammals and provide a mechanistic description of their interaction with cytoskeleton and tight junction proteins. We will then study molecular mechanisms dependent on Piezo detection of mechanical forces playing a role in intestinal epithelial turnover in vivo, by taking advantage of mouse experimental models. Based on this hypothesis, the specific scientific aims of the present project are as follows:1. Describe the role of Piezo1 for intestinal epithelial turnover in vivo. 2. Determine the relevance of Piezo1 for cell shedding as a process avoiding the accumulation of epithelial cell numbers. 3. Determine the relevance of Piezo1 for cell division as a process to replenish the intestinal epithelium. 4. Characterize Piezo-regulated molecular pathways in the human and murine gut in physiological conditions, with special focus on cytoskeleton and TJs. We will contribute to the mechanistic knowledge about the function of a recently identified molecule which is able to sense mechanical forces (Piezo1), and the downstream pathway which mediates signal transmission to the cytoskeleton and TJs proteins (Rho GTPases).Taken together, our project will provide innovative knowledge on mechanical force sensations and intercellular junctions as regulators of epithelial turnover in the gut, in the context of homeostasis and pathology.