Vascular Relations of Blood Cells and Proteins

血细胞和蛋白质的血管关系

• 批准号: 8502281
• 负责人: Richard E Waugh
• 金额: $ 164.38万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502281
• 关键词: Abnormal Cell; Address; Adhesions; Affect; Affinity; Agonist; Avidity; Behavior; Binding; Blood Cells; Blood Proteins; Blood Vessels; Cell Adhesion Molecules; Cells; Chemistry; Diffusion; Disease; Endothelial Cells; Event; Functional disorder; G-Protein-Coupled Receptors; Generations; Heart Diseases; Heterogeneity; Immobilization; Immunity; In Vitro; Inflammation; Inflammatory Response; Integrins; L-Selectin; Learning; Leukocytes; Ligation; Mechanics; Mediating; Molecular; Molecular Models; Neoplasm Metastasis; Pathology; Peripheral; Property; Research Design; Signal Pathway; Signal Transduction; Societies; Stimulus; Stroke; Surface; chemokine; clinically relevant; computer studies; in vivo; migration; molecular modeling; neutrophil; programs; research study; response; shear stress

The theme of this program project is the inter-relation of mechanics, chemistry and hydrodynamics as underlying mechanisms in normal and pathological peripheral vascular function, particularly the inflammatory response. Five projects are engaged in synergistic studies designed to reveal fundamental mechanisms underlying both normal and pathological phenomena in the peripheral vasculature with a central focus on neutrophil-endothelial interactions. Projects 1, 2, 3 and 4 have a common focus and employ complementary approaches to understand what governs integrin-mediated neutrophil attachment and migration. A particular emphasis is to relate behaviors observed in vitro (Projects 1, 2 and 3), where we can obtain precise understanding of regulatory mechanisms of adhesion, to clinically relevant events in vivo (Projects 2 and 4). Project 1 uses quantitative models and molecular approaches to understand signaling events connecting chemokine stimulus to integrin activation and cell immobilization in flow, as well as experiments on force generation during neutrophil crawling (with Projects 2 and 3). Project 2 uses molecular approaches to learn how integrin affinity is regulated in distinct regions of migrating cells both in vitro and in vivo. Project 3 uses single cell experiments to reveal how molecular diffusion and surface topography affect adhesion and the initiation of cell crawling, and to characterize the dynamics of signaling pathways leading to changes in integrin affinity and avidity. Project 4 focuses on the mechanisms underlying leukocyte-endothelial interaction in vivo, with emphasis on the functional consequences of heterogeneities in adhesion molecule expression, and signaling events in endothelial cells (EC) initiated by leukocyte ligation. Project 5 uses both computational and experimental approaches to study mechanisms related to cell capture, particularly with respect to ways that multiparticle hydrodynamics and shear stress may affect cell capture and cell activation (with Projects 1 and 4). In addition to computational studies to determine consequences of abnormal cell geometry on cell capture. Project 5, with Project 3, is exploring mechanotransduction mechanisms affecting L-selectin shedding and neutrophil response to agonists via G-protein coupled receptors. Peripheral vascular dysfunction is integral to pathology associated with the most serious diseases in western society, including heart disease, stroke, and cancer metastasis, as well as disorders involving inflammation and immunity. The underlying mechanisms for these involve mechanical forces, molecular interactions and cellular properties acting synergistically in ways that are uniquely addressed by this program.

该计划项目的主题是机械，化学和流体动力学的相互关联，作为正常和病理外周血管功能的潜在机制，尤其是炎症反应。五个项目参与了协同研究，旨在揭示周围脉管系统中正常现象和病理现象的基本机制，其主要重点是中性粒细胞 - 内皮相互作用。项目1、2、3和4具有共同的重点，并采用补充方法来了解整合素介导的中性粒细胞的依恋和迁移。一个特别的重点是将在体外观察到的行为（项目1、2和3）相关联，我们可以在其中精确理解粘附的调节机制与体内临床相关事件（项目2和4）。项目1使用定量模型和分子方法来了解将趋化因子刺激与整联蛋白激活和流动中的细胞固定的信号事件，以及中性粒细胞爬行期间对力产生的实验（项目2和3）。项目2使用分子方法来了解在体外和体内迁移细胞的不同区域中整合素亲和力如何调节。 Project 3使用单细胞实验来揭示分子扩散和表面形貌如何影响粘附和细胞爬行的启动，并表征信号通路的动力学，从而导致整联蛋白亲和力和亲和力的变化。项目4侧重于体内白细胞 - 内皮相互作用的基础机制，重点是异质性在粘附分子表达中的功能后果，以及白细胞结扎引起的内皮细胞（EC）的信号传导事件。项目5使用计算方法和实验方法来研究与细胞捕获有关的机制，尤其是在多粒子水动力学和剪切应力可能影响细胞捕获和细胞激活的方式方面（与项目1和4）。除了确定异常细胞几何形状在细胞捕获中的后果外。项目5和项目3正在探索通过G蛋白偶联受体对L-选择蛋白脱落和中性粒细胞反应的机械转导机制。 周围血管功能障碍是与西方社会中最严重的疾病有关的病理不可或缺的，包括心脏病，中风和癌症转移，以及涉及炎症和免疫力的疾病。这些这些程序的基本机制涉及机械力，分子相互作用和细胞特性，以该程序独特地解决的方式协同作用。