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Effects of Shear on Specific Adhesion Receptor Expression and Binding in the Bact

剪切对细菌中特异性粘附受体表达和结合的影响

基本信息

批准号：
7860401
负责人：
James D. Bryers
金额：
$ 7.33万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2009-06-05 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7860401
关键词：
Address Adherence Adhesions Adsorption Affect Affinity Albumins American Avidity Bacteria Bacterial Adhesins Bacterial Adhesion Benign Binding Biological Biological Models Biosensor Carbohydrates Cardiovascular system Cause of Death Cell Wall Cell surface Cells Cessation of life Chemistry Collagen Cues Data Development Devices Diagnostic Diffusion Ecosystem Electrostatics Epitopes Event Exposure to Extracellular Matrix Proteins Fibrinogen Fibronectin Receptors Fibronectins Figs - dietary Film Genes Genitourinary system Glycoconjugates Glycoproteins Goals Grant Growth Hospitals Human Immunoglobulins Implant In Vitro Infection Kinetics Ligand Binding Ligands Liquid substance Macor Mammalian Cell Mediating Medical Medical Device Microbial Biofilms Modeling Molecular Mucous Membrane Nose Nosocomial Infections Nutrient Organism Patients Physiological Physiology Plasma Plasma Proteins Polysaccharides Prevention Process Proteins Protocols documentation Research Signal Transduction Site Skin Staphylococcus epidermidis Surface System Terrorism Text Tissues Titanium United States National Institutes of Health Vaccines Virulence Virulence Factors Virulent Vitronectin Work adhesion receptor base cell growth cost density design implantable device inhibitor/antagonist macromolecule micro-total analysis system pathogen polyether urethane prevent public health relevance receptor receptor binding receptor expression shear stress small molecule wound

项目摘要

DESCRIPTION (provided by applicant): Bacterial specific adhesion to biological (host tissue) and synthetic substrata (e.g., biomedical devices) through receptor:ligand interactions with adsorbed molecules (e.g., blood plasma proteins, carbohydrates, and glycoconjugates) is a critical first step in a cascade of processes leading to biofilm formation; host tissue invasion, virulence and infection; and potentially death. Nosocomial infections are the fourth leading cause of death in the U.S. with >2 million cases annually (or ~10% of American hospital patients). About 60-70% of all such infections are associated with an implanted medical device causing >$4.5 billion medical costs in 2002 and ~99,000 deaths annually. One of the first steps in biofilm formation is the specific adhesion of bacterial cells via `adhesins' (or receptors) to ligand molecules present on the target surface. Prevention of this initial adherence binding could potentially abrogate biofilm formation and any subsequent infection. Development of small molecule therapies or vaccines to prevent specific adhesion to biomedical devices or, conversely, the fabrication of "lab-on-a-chip" arrays designed to promote adhesion and identify specific pathogens will require detailed information on bacterial specific binding events, under pertinent hydrodynamic conditions. Attempts to identify binding epitopes on both bacterial receptors and their immobilized ligands, in vitro, are complicated by (1) the inability to "present" the ligand in a defined and consistent orientation and (2) lack of detailed kinetics for adhesion receptor expression, as a function of cell growth and ambient hydrodynamic conditions, Based on prior work, we hypothesize that to precisely quantify bacterial specific adhesion will require (1) controlling the orientation and surface density of the binding ligand; (2) determination of the number, affinity and avidity of bacterial adhesion receptors; and (3) characterization of the binding interactions of the receptor:ligand pair - all under pertinent conditions of growth and fluid shear. Our ultimate goal is to develop a general protocol that will define bacterial adhesion receptor:ligand interactions, in their native states as a function of fluid shear - for both pure and mixed culture biofilms. PUBLIC HEALTH RELEVANCE: Our ultimate goal is to develop a general protocol that will define bacterial adhesion receptor:ligand interactions, in their native states as a function of fluid shear - for both pure and mixed culture biofilms. With NIH support, we will develop this protocol using the model pure culture system of Staphylococcus epidermidis (SE) binding to immobilized fibronectin (FN). Our specific aims in this two-year project will be: 1. Quantify, as a function of prevailing fluid shear, the specific binding of SE strains via fibronectin binding receptors (FNBR) to FN immobilized in a controlled orientation and known surface density. 2. Quantify the kinetics of FNBR adhesin receptor expression on SE surfaces, as function of bacterial growth condition and prevailing fluid shear; both as planktonic and adherent cells.

描述（由申请人提供）：细菌对生物（宿主组织）和合成基质（例如，生物医学装置）通过受体：配体与吸附分子的相互作用（例如，血浆蛋白、碳水化合物和糖缀合物）是导致生物膜形成、宿主组织侵入、毒性和感染以及潜在死亡的级联过程中的关键第一步。医院感染是美国第四大死亡原因，每年有超过200万例（或约10%的美国医院患者）。在所有这些感染中，约60-70%与植入式医疗设备有关，2002年造成> 45亿美元的医疗费用，每年约99，000人死亡。生物膜形成的最初步骤之一是细菌细胞通过“粘附素”（或受体）特异性粘附到靶表面上存在的配体分子。预防这种初始粘附结合可能会消除生物膜形成和任何后续感染。开发小分子疗法或疫苗以防止对生物医学设备的特异性粘附，或者相反地，制造设计用于促进粘附和识别特定病原体的“芯片实验室”阵列将需要在相关流体动力学条件下关于细菌特异性结合事件的详细信息。在体外鉴定细菌受体及其固定化配体上的结合表位的尝试由于以下原因而变得复杂：（1）不能以确定的和一致的取向“呈递”配体，以及（2）缺乏粘附受体表达的详细动力学，作为细胞生长和环境流体动力学条件的函数。我们假设为了精确地定量细菌特异性粘附将需要（1）控制结合配体的取向和表面密度;（2）确定细菌粘附受体的数量、亲和力和亲合力;和（3）受体：配体对的结合相互作用的表征-所有这些都在生长和流体剪切的相关条件下进行。我们的最终目标是开发一个通用的协议，将定义细菌粘附受体：配体的相互作用，在其天然状态作为流体剪切的函数-对于纯和混合培养生物膜。公共卫生相关性：我们的最终目标是开发一个通用的协议，将定义细菌粘附受体：配体的相互作用，在其天然状态作为流体剪切的函数-对于纯和混合培养生物膜。在美国国立卫生研究院的支持下，我们将使用表皮葡萄球菌（SE）与固定化纤维连接蛋白（FN）结合的模型纯培养系统开发此方案。在这个为期两年的项目中，我们的具体目标是：1。作为主要流体剪切力的函数，定量SE菌株通过纤连蛋白结合受体（FNBR）与以受控方向和已知表面密度固定的FN的特异性结合。2.定量SE表面上FNBR粘附素受体表达的动力学，作为细菌生长条件和主要流体剪切的函数;作为粘附细胞和粘附细胞。