CELLULAR AND DEVELOPMENTAL FUNCTIONS IN MENA

中东和北非地区的细胞和发育功能

• 批准号: 7193538
• 负责人: FRANK B GERTLER
• 金额: $ 30.33万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7193538
• 关键词: Actins; Adhesions; Animals; Axon; Biochemical; Biological; Biological Assay; Cell physiology; Cells; Cicatrix; Complement; Complex; Cyclic AMP-Dependent Protein Kinases; Development; Disease; Disseminated Malignant Neoplasm; Embryonic Development; Equilibrium; Family; Family member; Fibroblasts; Filament; Filopodia; Goals; Grant; Health; Human; Immune system; In Vitro; Inflammatory; Intercellular Junctions; Kinetics; Link; Listeria; Localized; Mediating; Microfilaments; Modeling; Molecular; Morphogenesis; Movement; Mus; Mutate; Neurons; Phagocytosis; Phenotype; Phosphorylation; Physiology; Play; Process; Proteins; Regulation; Research Personnel; Role; Signal Transduction; Signaling Protein; Site; Testing; Transgenic Animals; Vascular Endothelium; Visual; Wound Healing; axon guidance; cell growth regulation; cell motility; cell type; in vivo; member; migration; mutant; polymerization; programs; research study; response; tissue regeneration; vasodilator-stimulated phosphoprotein

DESCRIPTION (provided by applicant): Regulation of actin dynamics plays an integral role in many processes important for human health. Morphogenesis during embryonic development involves extensive migration, establishment of cell: cell contacts, regulated secretion and internalization of signaling proteins and numerous other cellular processes dependent upon dynamic actin remodeling. Disease-related processes including metastatic cancer, inflammatory disorders, wound repair and tissue regeneration all involve actin-dependent mechanisms. Cell migration requires coordinated regulation of cellular protrusions, adhesion, contractile forces and rear detachment. Ena/VASP proteins regulate the protrusive step of motility in fibroblasts by controlling the geometry of actin networks within lamellipodia, promoting formation of longer, less branched actin networks. Ena/VASP also likely play key roles in other actin-dependent processes such as phagocytosis, formation of cell: cell junctions and regulation of the vascular endothelium. We hypothesis that Ena/VASP proteins act as key convergence points, integrating specific signals and converting them into dynamic cytoskeletal remodeling. This grant outlines experiments to identify other migration and actin-dependent processes that utilize Ena/VASP function in vivo through analysis of mice lacking two or all three family members. W will also combine cell biological and biochemical approaches to continue our efforts to elucidate mechanisms of Ena/VASP function and regulation. We will also characterize interactions between Ena/VASP and NESH, a member of the Abi family of adaptor molecules that localizes to protruding lamellipodia and filopodia. Interestingly, Abi proteins are present in complexes that regulate the SCAR/WAVE family of Arp2/3 activating proteins, suggesting that NESH could serve as a link between Ena/VASP and SCAR/WAVE function.

描述（由申请人提供）：肌动蛋白动力学的调节在许多对人类健康重要的过程中发挥着不可或缺的作用。胚胎发育过程中的形态发生涉及广泛的迁移、细胞：细胞接触的建立、信号蛋白的调节分泌和内化以及依赖于动态肌动蛋白重塑的许多其他细胞过程。疾病相关过程，包括转移性癌症、炎症性疾病、伤口修复和组织再生，都涉及肌动蛋白依赖性机制。细胞迁移需要细胞突起、粘附、收缩力和后部脱离的协调调节。 Ena/VASP 蛋白通过控制板状伪足内肌动蛋白网络的几何形状来调节成纤维细胞运动的前伸步骤，促进更长、分支较少的肌动蛋白网络的形成。 Ena/VASP 也可能在其他肌动蛋白依赖性过程中发挥关键作用，例如吞噬作用、细胞形成：细胞连接和血管内皮的调节。我们假设 Ena/VASP 蛋白充当关键汇聚点，整合特定信号并将其转化为动态细胞骨架重塑。该资助概述了通过分析缺乏两个或全部三个家族成员的小鼠来识别利用体内 Ena/VASP 功能的其他迁移和肌动蛋白依赖性过程的实验。 W还将结合细胞生物学和生化方法，继续努力阐明Ena/VASP功能和调节机制。我们还将表征 Ena/VASP 和 NESH 之间的相互作用，NESH 是 Abi 接头分子家族的成员，定位于突出的板状伪足和丝状伪足。有趣的是，Abi 蛋白存在于调节 Arp2/3 激活蛋白的 SCAR/WAVE 家族的复合物中，这表明 NESH 可以充当 Ena/VASP 和 SCAR/WAVE 功能之间的联系。