Mechanical Regulation of Selectin-Ligand Binding Kinetics

选择素-配体结合动力学的机械调节

基本信息

批准号：
7996050
负责人：
RODGER PAUL MCEVER
金额：
$ 53.2万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-15 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7996050
关键词：
Adhesions Affect Animals Attention Binding Blood Circulation Blood Vessels Cell Adhesion Cell physiology Cells Computer Simulation Crystallography Data Dependence Diffusion Dimensions Disease Dissociation Docking Endothelium Environment Epidermal Growth Factor Equation Frequencies Gene Targeting Glycoconjugates High Endothelial Venule In Vitro Infection Inflammation Inflammatory Inflammatory Response Injury Inorganic Sulfates Kinetics Knock-in Mouse L-Selectin Lead Lectin Leukocytes Ligand Binding Ligands Mechanics Mediating Microspheres Minor Modeling Molecular Molecular Conformation Molecular Models Molecular Structure Mucins Mus Mutagenesis Mutation P-selectin ligand protein Pathology Phenotype Physiological Physiology Recruitment Activity Regulation Selectins Signal Transduction Site Slide Solutions Structure Structure-Activity Relationship Surface Testing Thrombosis Time Tissues Unspecified or Sulfate Ion Sulfates Variant Vascular Endothelium Work base flexibility in vivo insight mathematical model molecular dynamics molecular modeling mutant novel therapeutic intervention postcapillary venule public health relevance research study simulation single molecule sulfation

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to elucidate the mechanical regulation of molecular interactions between selectins and glycoconjugate ligands, which mediate the first step of a multistep adhesion and signaling cascade for circulating leukocytes to attach to and migrate across vascular endothelium at sites of tissue injury or infection. These interactions are crucial, because their malfunction can result in a number of inflammatory and thrombotic disorders. Selectin-ligand interactions are regulated mechanically as they take place in the hydrodynamic environment of the circulation. Our hypothesis is that mechanical regulation of selectin-ligand binding kinetics results from specific atomic-level interactions that are dictated by the structures of these molecules. Force regulates bond dissociation by changing the energy landscape of these interactions and/or forming new interactions during force-induced fit and/or conformational changes, thereby eliciting slip and catch bonds. Transport regulates bond formation by influencing collision frequency and encounter time between interacting molecules, modulating the dependence of association kinetics on intrinsic docking. Since selectin-ligand binding kinetics determines cellular function under flow, including tethering, rolling, and aggregation, relatively minor structural differences that alter atomic-level interactions may have major consequences for physiology and pathology. This broad hypothesis will be tested in three integrated specific aims: 1) Define impact of structural variations in selectins and ligands on their interactions, 2) Define selectin-ligand interactions at the atomic level by molecular dynamics simulations, and 3) Define the consequences of ligand-specific alterations in L-selectin-dependent adhesion in vivo. The three specific aims combine experimental, theoretical and computational approaches, include in silico, in vitro, and in vivo studies, and span multiple scales from atomic-level mechanisms, single-cell and single-molecule kinetic/mechanics experiments, to whole animal physiology. This systematic study will clarify how the mechanical regulation of selectin-ligand binding kinetics enables leukocytes to adhere to blood vessel wall in the hydrodynamic environment of the circulation. Decoding how molecular structure determines this regulation will provide key insights into vascular physiology and pathology. As a result, the data may offer new therapeutic approaches to inhibiting pathological cell adhesion during inflammation and thrombosis. PUBLIC HEALTH RELEVANCE: We propose to elucidate the mechanical regulation of molecular interactions between selectins and glycoconjugate ligands, which mediate circulating white blood cells to adhere to vascular surface at sites of tissue injury or infection. This regulation is crucial because malfunction of selectin-ligand interactions can result in a number of inflammatory and thrombotic disorders. The data may offer new therapeutic approaches to inhibiting pathological cell adhesion during inflammation and thrombosis.

描述（由申请人提供）：该提案的目的是阐明Selectins和糖缀合物配体之间分子相互作用的机械调节，该配体介导了多氏粘附和信号级联的第一步，以循环循环白细胞，以附着在血管造成的内皮损伤或迁移的是在血管内部损伤或迁移的组织或迁移。这些相互作用至关重要，因为它们的故障会导致许多炎症性和血栓性疾病。选择素 - 配体相互作用在循环的流体动力环境中进行机械调节。我们的假设是，选择素 - 配体结合动力学的机械调节是由特定的原子水平相互作用产生的，这些相互作用由这些分子的结构决定。力通过改变这些相互作用的能量格局和/或在力诱导的拟合和/或构象变化期间形成新相互作用，从而调节键的解离，从而引起滑移和捕获键。运输通过影响相互作用分子之间的碰撞频率和遇到时间来调节键的形成，从而调节关联动力学对内在对接的依赖性。由于选择素 - 配体结合动力学决定了流动下的细胞功能，包括绑扎，滚动和聚集，因此改变原子水平相互作用的相对较小的结构差异可能会对生理和病理产生重大影响。这一广泛的假设将以三个综合的特定目的进行检验：1）定义选择素和配体对其相互作用的结构变化的影响，2）通过分子动力学模拟在原子级上定义Selectin-grigand-gand-gand-gand-gand-gand-gand互动，而3）定义了LIGAND特异性变化在L-SELECTIN依赖性依赖性依赖性粘附率in Vivo中的影响。这三个特定的目的结合了实验，理论和计算方法，包括在硅，体外和体内研究中，以及从原子级机制，单细胞和单分子动力学/力学/力学实验（全动物生理学）跨越多个尺度。这项系统的研究将阐明如何在循环的流体动力环境中粘附的精蛋白 - 配体结合动力学的机械调节如何使白细胞粘附在血管壁上。解码分子结构如何确定该调节将为血管生理和病理学提供关键的见解。结果，数据可能会提供新的治疗方法来抑制炎症和血栓形成过程中病理细胞粘附。公共卫生相关性：我们建议阐明Selectins和糖缀合物配体之间分子相互作用的机械调节，这些配体在组织损伤或感染部位介导循环白细胞以粘附在血管表面上。该调节至关重要，因为选择素 - 配体相互作用的故障可能导致许多炎症性和血栓性疾病。该数据可能会提供新的治疗方法来抑制炎症和血栓形成期间病理细胞粘附。