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

物种特异性方式的接头介导的整合素信号转导的分子机制

• 批准号: 10540367
• 负责人: Jinhua Wu
• 金额: $ 48.15万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540367
• 关键词: Adaptor Signaling Protein; Autoimmune Diseases; Basic Science; Cardiovascular Diseases; Cell Adhesion; Cell Adhesion Molecules; Cell membrane; Data; Defect; Development; Disease; Event; Functional disorder; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Inflammatory; Integrins; Laboratories; Link; Mediating; Molecular; Monomeric GTP-Binding Proteins; Post-Translational Protein Processing; Protein Isoforms; Proteins; Public Health; Regulation; Research; Signal Pathway; Signal Transduction; Specificity; T-Cell Proliferation; Therapeutic; Therapeutic Intervention; Thrombosis; Translational Research; cell motility; inhibitor; insight; interest; molecular modeling; peptidomimetics; programs; therapeutically effective

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.

项目摘要/摘要 我的实验室对了解细胞黏附的分子机制和 整合素和相关的小GTP酶介导的运动性，并将这些发现应用于 潜在治疗益处的新型抑制剂。整合素是一种细胞黏附分子，可以转导 信号通过质膜在两个方向上。血栓疾病、心血管疾病、T细胞 增殖缺陷和许多自身免疫性疾病与整合素的错误调节有关 表达及其活性。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事件的分子模型不准确，缺乏对 不同整合素种类的调节，特殊的双重GTP酶特异性的未知机制 它们的效应器蛋白，以及缺乏针对细胞内适配器的抑制剂。 我们已经获得了弥合这一差距的大量初步数据。实验室下一步的主要目标 五年的时间是研究接头和整合素的信号机制，重点是连接 具有特定整合素物种和相关GTP酶的异构体和翻译后修饰，以及 开发一类新的适配器蛋白抑制剂来控制整合素的功能。拟议的研究包括这两项 基础研究和翻译研究，反映了我们研究的范围不断扩大 程序。我们的积极努力无疑将支持我们实现攻克整合素的总体目标 通过更有效的治疗干预措施减少与疾病相关的疾病。