Endothelial glycocalyx shedding in septic injury

脓毒性损伤中的内皮糖萼脱落

基本信息

批准号：
10532364
负责人：
MACK H WU
金额：
$ 46.58万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10532364
关键词：
3-Dimensional Address Affect Age Animal Model Animal Organ Animals Bacteremia Bacterial Infections Bacterial Pneumonia Bacterial Toxins Biological Assay Biological Markers Blood Circulation Blood Vessels Cells Circulation Communicable Diseases Complement Complex Coupled Critical Illness Cytoskeleton Development Diagnostic Disease Disintegrins Endothelial Cells Endothelium Enzymes Exposure to Extravasation Functional disorder Future Glycocalyx Glycoproteins Glycosaminoglycans Goals Human Immune response Infection Inflammatory Inflammatory Response Injury Intercellular Junctions Invaded Knowledge Life Link Lipopolysaccharides Liquid substance Lung Lung infections Measures Mediating Mediator Mesentery Metalloproteases MicroRNAs Microcirculation Modeling Molecular Molecular Target Morphology Multiple Organ Failure Nanotechnology Organ Pathogenesis Pathologic Pathway interactions Peptides Perfusion Permeability Pharmaceutical Preparations Plasma Play Prevention Process Production Property Proteins Proteoglycan Proteomics Pseudomonas aeruginosa Regional Perfusion Research Personnel Role Sepsis Signal Transduction Structure Surface Techniques Testing Therapeutic Time Tissues Toxin Translating Up-Regulation Vascular Endothelial Cell Work blood perfusion comparative design diagnostic tool effective therapy experimental study extracellular infectious disease treatment innovation innovative technologies insight intravital microscopy knockout gene microscopic imaging mortality multidisciplinary nanoimaging new therapeutic target novel novel diagnostics optoacoustic tomography overexpression pathogen pharmacologic response response to injury septic sex syndecan systemic inflammatory response technology platform therapeutically effective tissue oxygenation ultra high resolution vascular inflammation

项目摘要

PROJECT SUMMARY/ABSTRACT Sepsis is a critical illness arising from dysregulated host response to infection where invading pathogens elicit an adverse systemic inflammatory response that affects multiple organs and tissues. Currently, there are limited therapies that effectively treat this disease. The overarching goal of our work is to identify new molecular targets that can potentially serve as diagnostics or therapeutics for prevention and treatment of sepsis. This project focuses on glycocalyx shedding as not merely a consequence, but a critical cause, of inflammatory injury. Specifically, we hypothesize that bacterial infection promotes disintegrin metalloprotease (ADAM) upregulation and activity to shed glycocalyx molecules on endothelial surface and release their fragments into the circulation, which act as inflammatory signals to mediate microcirculatory dysfunction and barrier leakage by triggering endothelial cytoskeleton-junction responses. This novel concept will be tested by completing two aims: Aim 1 to characterize the molecular property of glycocalyx shedding products and function in microvascular inflammation during sepsis; Aim 2 to elucidate the molecular mechanisms of endothelial glycocalyx shedding and barrier injury. We propose a multifaceted approach based on an innovative design that integrates peptidomics, proteomics and nanotechnology with multispectral photoacoustic tomography, super-resolution confocal and 3D intravital microscopic imaging. Functionally viable human lungs and microvessels serve as the primary models, which are complemented by animal models and cell experiments. Microvascular barrier structure and function will be examined in-depth at the organ, tissue and cell levels under pathophysiologically relevant conditions of bacterial infection. We expect to gain novel insights that will not only fill the knowledge gaps in understanding the molecular mechanisms of septic injury, but also contribute to the development of effective therapeutics against infectious diseases. The proposed human organ studies further highlight the translational values of our work.

项目概要/摘要脓毒症是一种严重疾病，是由于宿主对感染的反应失调而引起的，其中入侵的病原体引起影响多个器官和组织的不良全身炎症反应。目前，数量有限有效治疗这种疾病的疗法。我们工作的首要目标是确定新的分子靶点可以作为预防和治疗脓毒症的诊断或治疗方法。这个项目重点关注糖萼脱落不仅是炎症损伤的结果，而且是炎症损伤的关键原因。具体来说，我们假设细菌感染促进解整合素金属蛋白酶 (ADAM) 上调以及在内皮表面脱落糖萼分子并将其片段释放到循环中的活性，作为炎症信号，通过触发介导微循环功能障碍和屏障渗漏内皮细胞骨架连接反应。这个新颖的概念将通过完成两个目标来进行测试：目标 1 表征糖萼脱落产物的分子特性及其在微血管炎症中的功能败血症期间；目标 2 阐明内皮糖萼脱落和屏障损伤的分子机制。我们提出了一种基于创新设计的多方面方法，该设计整合了肽组学、蛋白质组学和具有多光谱光声断层扫描、超分辨率共焦和 3D 活体成像的纳米技术显微成像。功能可行的人肺和微血管作为主要模型，并辅以动物模型和细胞实验。微血管屏障的结构和功能在细菌病理生理学相关条件下，在器官、组织和细胞水平上进行深入检查感染。我们期望获得新颖的见解，这不仅可以填补理解领域的知识空白脓毒症损伤的分子机制，也有助于开发有效的治疗方法传染病。拟议的人体器官研究进一步凸显了我们工作的转化价值。