Hydrodynamic Interactions and Cell Deformation in Neutrophil Adhesion

中性粒细胞粘附中的流体动力学相互作用和细胞变形

• 批准号: 8377770
• 负责人: Michael R. King
• 金额: $ 30.19万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8377770
• 关键词: ABL1 gene; Address; Adhesions; Adhesives; Affinity; Appearance; Behavior; Binding; Binding Proteins; Biological Assay; Biophysics; Blood Cells; Blood Proteins; Blood Vessels; Blood flow; Cell Adhesion; Cell Communication; Cell Line; Cell Shape; Cells; Cellular Morphology; Chemotactic Factors; Collaborations; Communities; Complex; Computer Simulation; Cytoplasmic Tail; Cytoskeleton; Data; Dose; Endothelial Cells; Endothelium; Engineering; Environment; Exposure to; Extravasation; Flow Cytometry; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; Goals; Guanine Nucleotide Dissociation Inhibitors; HL-60 Cells; Human; Immune System Diseases; Immune response; In Vitro; Inflammation; Inflammatory; L-Selectin; Lateral; Length; Leukocyte Rolling; Leukocytes; Life; Ligands; Liquid substance; Measurable; Measurement; Measures; Mechanics; Mediating; Modeling; Molecular; Mus; P-selectin ligand protein; Paper; Peptides; Phase; Physics; Physiological; Platelet Activating Factor; Platelet Activating Factor Activation; Probability; Process; Protein Kinase; Proteins; Regulation; Reperfusion Injury; Research; Resistance; Retinal Cone; Role; Selectins; Shapes; Signal Transduction; Signaling Molecule; Site; Small Interfering RNA; Stream; Surface; Suspension substance; Suspensions; TNF-alpha converting enzyme; Testing; Tissues; Work; c-abl Proto-Oncogenes; cell motility; cell type; computer studies; crosslink; immune function; in vivo; inhibitor/antagonist; mitogen-activated protein kinase p38; neutrophil; novel; platelet activating factor receptor; programs; protein aminoacid sequence; receptor; receptor expression; research study; response; shear stress; sialyl Lewis x; simulation; single molecule; small molecule; surface coating; venule

The central goal of Project 5 is to understand the interplay between fluid shear stress, cell morphology, and L-selectin expression on the dynamics of neutrophil tethering and rolling on the endothelium. We will use a combination of state-of-the-art computational simulations of receptor-mediated cell adhesion under flow, in vitro experiments with isolated human neutrophils and neutrophil-like cell lines in well-deflned fluid shear environments, and collaborative invesfigafion with other projects. The mulfiparticle adhesive dynamics simulafion developed by the PI, enables the invesfigafion of previously unaddressed problems such as the influence of non-spherical shape on the physics of leukocyte rolling, and computational and experimental study of L-selecfin shedding and mechanosensing. The multitude of physical determinants combining to control neutrophil inflammatory recruitment, including receptor expression, activation state, cell shape, local flow environment, and cell-cell collisions are highly complex and nonlinear and so we have taken a systematic integrated engineering approach to elucidate these behaviors. The proposed work is organized around three specific aims. Aim 1: Selecfin-Mediated Tethering and Rolling of Activated Leukocytes: In this aim we will use mulfiparticle adhesive dynamics simulafions of acfivated cell shapes, and detailed analysis of in vivo observations of activated cell rolling, to study the dynamics of non-spherical cell adhesion. Aim 2: Mechanisms of L-Selecfin Mechanotransducfion and Shedding During Rolling. This aim will explore the molecular mechanisms of mechanical shedding in flow chamber experiments with primary neutrophils and an altered neutrophil-like cell line. Aim 3: Shear-Induced Resistance to Activation via Chemoattractant GPCRs. In this aim, we will study the quantitafive dynamics of the shear stress-dependent GPCR-mediated response of neutrophils to fMLP and platelet activating factor (PAF). Together, the proposed research will determine for the first fime how the physics of nonspherical leukocyte shape, and the mechanical response of neutrophil receptors at the single molecule level, influence the dynamics of cell tethering and rolling to selecfin-presenfing endothelium under physiological flow.

项目5的核心目标是了解流体剪切应力，细胞形态和 L-选择素在内皮上嗜中性粒细胞的动力学上的表达。我们将使用一个 在流动下的受体介导的细胞粘附的最新计算模拟中的结合，在 在持久的流体剪切中，用分离的人类中性粒细胞和中性粒细胞样细胞系进行体外实验 环境，以及与其他项目的协作Invesfigafion。 Mulfiparpicle粘合剂动力学 由PI开发的模拟，实现了以前未解决的问题（例如 非球形形状对白细胞滚动物理的影响以及计算和实验性的影响 L-链球芬的研究和机械感应。众多的物理决定因素合并到 控制中性粒细胞炎症募集，包括受体表达，激活状态，细胞形状，局部 流动环境和细胞细胞碰撞是高度复杂且非线性的，因此我们采取了 系统的集成工程方法来阐明这些行为。拟议的工作是组织的 大约三个具体目标。 AIM 1：Selecfin介导的活性白细胞的束缚和滚动：在此中 目的，我们将使用Mulfiparfipicle的粘合剂动力学模拟细胞形状的模拟，并详细分析 体内观察活化的细胞滚动，研究非球细胞粘附的动力学。目标2： L-固定机械转换和脱落的机理。这个目标将探索 原代嗜中性粒细胞和流量室实验中机械脱落的分子机制 中性粒细胞样细胞系改变。 AIM 3：剪切诱导的抗性性通过化学吸引剂 GPCR。在此目标中，我们将研究剪切应力依赖性GPCR介导的定量动力学 中性粒细胞对FMLP和血小板激活因子（PAF）的反应。拟议的研究将在一起 确定第一个唱片的非球体白细胞形状的物理学和机械响应如何 单分子水平的嗜中性粒细胞受体的影响，影响细胞束缚和滚动的动力学 在生理流程下selecfin-presenfing内皮。