整合素αvβ3和纤连蛋白FN相互作用的力学调控机制

整合素αvβ3和纤连蛋白FN间的相互作用，在多种肿瘤细胞的恶性转移过程中起到至关重要的作用。αvβ3和FN的键合和解离，受到血流剪应力环境的调制。揭示其中的力-化学偶联的反应动力学机制，对于深入了解多种肿瘤的发生和发展过程，设计相应新型抗肿瘤药物等，均具有重要意义。本项目以αvβ3/FN分子系统调控的黑色素肿瘤细胞黏附为实验模型，以平行平板流动腔实验、原子力显微镜实验和分子动力学模拟为技术手段，研究血流剪切应力下αvβ3/FN分子对的结合和解离速率；探明影响其键形成的主要因素；定量刻画αvβ3/FN之键离解的力学调控机制；揭示力依赖性αvβ3/FN相互作用的分子结构基础，标定关键氨基酸残基的位置，为相关创新药物的设计开发提供有效信息和新思路。

The integrin (αvβ3)-fibronectin (FN) interaction plays a key role in growth and dissemination of malignant tumor metastasis. The association and dissociation of αvβ3 with FN are regulated not only by the specific molecular kinetic properties but also by the blood flows. The aim of this grant is to reveal the force-regulation mechanism of αvβ3/FN interaction for more clear understanding on the initiation, progression and metastasis of tumors. In this grant, the adhesion of melanoma mediated by αvβ3/FN interaction will be studied, and flow chamber experiment, atomic force microscope experiment，and steered molecular dynamic simulation technique will be combined and used in these integrated specific aims: Measure kinetic constants of αvβ3/FN bond formation (on-rates) and dissociation (off-rates) under force; Determine what the key factor is during bond formation; Quantify the force-dependent regulation mechanism of bond dissociation; Elucidate the molecular structural foundation of force-dependent αvβ3/FN interaction with encoding the sites of key amino acid residues. The results would offer some new therapeutic approaches for the development and clinical implementation of novel anti-cancer treatments.