Endothelial glycocalyx shedding in septic injury

脓毒性损伤中的内皮糖萼脱落

• 批准号: 10374295
• 负责人: MACK H WU
• 金额: $ 47.07万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 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/10374295
• 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; Cells; 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; Inflammation; Inflammatory; Inflammatory Response; Injury; Intercellular Junctions; Invaded; Knowledge; Life; Link; Lipopolysaccharides; Liquid substance; Lung; Lung infections; Measures; Mediating; Mediator of activation protein; Mesentery; Metalloproteases; MicroRNAs; Microcirculation; Modeling; Molecular; Molecular Target; Morphology; Multiple Organ Failure; Nanotechnology; Organ; Pathogenesis; Pathologic; Pathway interactions; Peptides; Perfusion; Permeability; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Prevention; Process; Production; Property; Proteins; Proteoglycan; Proteomics; Pseudomonas aeruginosa; Research Personnel; Resolution; Role; Sepsis; Signal Transduction; Structure; Surface; Techniques; Testing; Therapeutic; Time; Tissues; Toxin; Translating; Up-Regulation; Work; base; 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; response; response to injury; septic; sex; syndecan; systemic inflammatory response; therapeutically effective; tissue oxygenation

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.

项目总结/摘要 脓毒症是一种严重的疾病，由宿主对感染的反应失调引起，其中入侵的病原体引起 一种影响多个器官和组织的不良全身炎症反应。目前， 有效治疗这种疾病的方法。我们工作的首要目标是确定新的分子靶点 其可以潜在地用作预防和治疗脓毒症的诊断剂或治疗剂。这个项目 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。 具体而言，我们假设细菌感染促进解整合素金属蛋白酶（ADAM）上调 以及在内皮表面上脱落糖萼分子并将其片段释放到循环中的活性， 其作为炎症信号通过触发微循环障碍和屏障渗漏来介导微循环障碍和屏障渗漏 内皮细胞连接反应。这一新颖的概念将通过完成两个目标来检验：目标1至 表征糖萼脱落产物的分子特性及其在微血管炎症中的作用 目的2阐明脓毒症时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，将肽组学，蛋白质组学和 纳米技术与多光谱光声断层扫描，超分辨率共聚焦和3D活体 显微成像功能可行的人肺和微血管作为主要模型， 辅以动物模型和细胞实验。微血管屏障的结构和功能， 在细菌感染的病理生理相关条件下，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的见解，不仅填补知识空白，了解 脓毒性损伤的分子机制，而且有助于发展有效的治疗方法， 传染病拟议的人体器官研究进一步突出了我们工作的转化价值。