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: 10330819
• 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/10330819
• 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 我的实验室有兴趣了解细胞粘附和 由整合素和相关的小GTPases介导的运动性，并将这些发现应用于开发 新的抑制剂，以获得潜在的治疗益处。整合素是细胞粘附分子，可转导 两个方向的质膜跨质膜的信号。血栓性疾病，心血管疾病，T细胞 扩散缺陷和许多自身免疫性疾病已与整合素的不利相关 表达及其活性。整联蛋白和相关信号通路领域的主要差距包括 整合素激活剂介导的信号事件的不准确分子模型，对 调节不同整合素种的调节，是奇特的双重GTPase特异性的未知机制 它们的效应蛋白，以及缺乏针对细胞内衔接子的抑制剂。 我们获得了大量的初步数据来弥合这一差距。下一个实验室的主要目标 五年是研究适配器和整联蛋白的信号传导机制，重点是连接 与特定整合素物种和相关GTPases的同工型和翻译后修饰的以及 开发一类新的衔接蛋白抑制剂来控制整联蛋白功能。拟议的研究包括 基础研究和翻译研究，反映了我们研究中不断扩展的研究范围 程序。我们的巨大努力无疑将支持我们实现征服整合素的总体目标 相关疾病通过更有效的治疗干预措施。