Molecular Mechanisms Underlying Adaptor-Mediated Integrin Signaling in a Species-Specific Manner

项目总结/摘要 我的实验室对了解细胞粘附的分子机制很感兴趣， 整合素和相关的小GTP酶介导的运动，并将这些发现应用于 新型抑制剂的潜在治疗效益。整合素是细胞粘附分子， 信号在两个方向上穿过质膜。血栓性疾病，心血管疾病，T细胞 增殖缺陷和许多自身免疫性疾病都与整合素的失调有关 表达及其活动。整合素和相关信号通路领域的主要空白包括 整合素激活剂介导的信号传导事件的分子模型不准确， 不同整合素种类的调节，独特的双重GT3特异性的未知机制 以及缺乏针对细胞内衔接子的抑制剂。 我们已经获得了大量的初步数据来弥补这一差距。下一个实验室的主要目标是 五年的时间是研究衔接子和整合素的信号机制，重点是连接 特异性整合素种类和相关GTP酶的同种型和翻译后修饰，以及 开发一类新的衔接蛋白抑制剂来控制整联蛋白的功能。拟议的研究包括 基础研究和转化研究，这反映了我们的研究范围不断扩大 程序.我们的积极努力无疑将支持我们实现征服整合素的总体目标 通过更有效的治疗干预来治疗相关疾病。

PROJECT SUMMARY/ABSTRACT My laboratory is interested in understanding the molecular mechanisms underlying cell adhesion and motility mediated by integrins and related small GTPases, and applying these findings to the development of new class of inhibitors for potential therapeutic benefits. Integrins are cell adhesion molecules that transduce signals across the plasma membrane in both directions. Thrombotic disorders, cardiovascular diseases, T cell proliferation defects, and many autoimmune diseases have been linked to the misregulation of integrin expression and its activity. The major gaps in the field of integrin and related signaling pathways include inaccurate molecular models of signaling events mediated by the integrin activator, a lack of understanding to the regulation of different integrin species, unknown mechanism underlying the peculiar dual GTPase specificity of their effector protein, and a lack of inhibitors targeting intracellular adaptors. We have obtained substantial preliminary data to bridge this gaps. The main goals of the lab for the next five years are to investigate the signaling mechanisms of the adaptors and integrins, focusing on the connection of isoforms and posttranslational modifications with specific integrin species and related GTPases, and to develop a new class of adaptor protein inhibitors to control integrin functions. The proposed studies include both basic research and translational research, which reflect an ever-expanding scope of the research in our research program. Our vigorous efforts would undoubtedly support us to achieve the overall goal of conquering integrin related diseases by more effective therapeutic interventions.