Glycocalyx repair in sepsis using liposomal carriers of preassembled glycocalyx

使用预组装糖萼的脂质体载体修复脓毒症中的糖萼

基本信息

批准号：
10428550
负责人：
MICHAEL S GOLIGORSKY
金额：
$ 54.12万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10428550
关键词：
Affect Antithrombin III Bacteremia Biodistribution Blood Vessels Carbohydrates Cardiovascular Diseases Cell Surface Receptors Cell membrane Competence Detection Dose Electron Microscopy Endothelial Cells Endothelium Exhibits Feedback Formulation Functional disorder Generations Glycocalyx Gold Growth Factor Half-Life Heparin Image Impairment Implant In Vitro Inflammatory Intervention Investigation Kidney Kidney Diseases Label Leukocyte Trafficking Life Liposomes Measurement Metabolic Clearance Rate Metabolic Diseases Microcirculation Modification Monitor Morbidity - disease rate Multiple Organ Failure Mus Nitric Oxide Nitric Oxide Donors Organ Oxidative Stress Pathogenicity Pharmacology Production Renal function Sepsis Septicemia Superoxide Dismutase Surface Survival Rate Testing Therapeutic Vascular Permeabilities Vasodilation Vasodilator Agents arteriole base chemokine clinical practice design endothelial repair extracellular functional restoration glucuronyl glucosamine glycan sulfate heart function hemodynamics improved in vitro testing in vivo in vivo evaluation intravenous injection intravital imaging liposome vector liver function mechanical force mechanotransduction mortality nanoliposome novel strategies novel therapeutics polymicrobial sepsis prevent pulmonary function receptor reconstitution repaired response restoration sensor septic shear stress tool vasomotion

项目摘要

ABSTRACT Endothelial glycocalyx (EG), a carbohydrate-rich outermost surface layer, is a guardian of vascular functions. It is a sensor of the shear stress-activated endothelial nitric oxide production and flow-induced vasodilation, harbinger of growth factors, extracellular superoxide dismutase and anti-thrombin III, EG is a regulator of vascular permeability and leukocyte trafficking across the vascular wall, and it protects receptors from hyperstimulation by shielding them. EG is degraded in diverse cardiovascular, metabolic and renal diseases, thus leading to impairment of all the above functions. One of these conditions precipitating the loss of EG is septicemia, which is associated with high morbidity and mortality. We observed that mice with the polymicrobial sepsis exhibit a drastic reduction in the global volume of EG. Therefore, expeditious restoration of EG represents a rational pathogenetic therapy. We have recently designed, synthesized and tested in vitro, ex vivo and in vivo liposomal nanocarriers of preassembled glycocalyx. This pharmacological intervention improved mechanotransduction and nitric oxide synthesis, flow-induced vasodilation and renal microcirculation in endotoxemic mice. We have presently designed and synthesized the second generation of liposomal nanocarriers of preassembled glycocalyx featuring “stealth” liposomes with increased half-life, gold-label, as well as an array of possible modifications and demonstrated that they significantly improved survival of mice injected with the lethal dose of LPS. The present proposal is aimed at exploration of validity and efficacy of this pharmacologic approach in sepsis. We describe the steps to refine liposomal nanocarriers of preassembled glycocalyx, monitoring of the fate of these gold-labeled liposomes – their fusion with the plasma membrane, intracellular traffic, half-life in the vasculature. Thereafter we shall determine the effect of intravenous injection of liposomal nanocarriers on the course of sepsis and associated with it hemodynamic perturbations and the rate of functional restoration of affected organs. Proposed studies should not only refine this novel therapeutic tool but may also establish a pharmacologic approach to ameliorate sepsis-induced multiorgan failure.

抽象的内皮糖脂（例如）是一种碳水化合物富含碳水化合物的表面层，是监护人血管功能。它是剪切应力激活的内皮一氧化氮的传感器生产和流动诱导的血管舒张，生长因子的预兆，细胞外超氧化物歧化酶和抗凝血酶III，EG是血管通透性和白细胞贩运血管墙，它可以保护接收者免受通过屏蔽它们过度刺激。例如在潜水员心血管，代谢中降解和肾脏疾病，从而导致上述所有功能受损。其中之一引起EG丧失的疾病是败血病，与高有关发病率和死亡率。我们观察到与多数型败血症的小鼠暴露了 EG的全球体积的急剧减少。因此，迅速恢复代表一种理性的致病疗法。我们最近设计，合成和在体外测试，体内和体内脂质体纳米载体的糖脂前糖体载体。这种药物干预改善了机械转移和一氧化氮内毒素小鼠的合成，流动诱导的血管舒张和肾小管循环。我们已经设计并合成了第二代脂质体预组装糖脂的纳米载体，具有“隐形”脂质体，并增加半身寿命，金标签以及一系列可能的修改，并证明了这一点它们显着提高了注射致命剂量LPS的小鼠的存活。目前的建议旨在探索该药理的有效性和效率败血症的方法。我们描述了完善脂质体纳米载体的步骤预成型的糖脂，监测这些金标记的脂质体的命运 - 它们与质膜融合，细胞内交通，脉管系统中的半衰期。此后，我们将确定静脉注射脂质体纳米载体的作用在败血症的过程中，与IT相关的血液动力学扰动和速率受影响器官的功能恢复。拟议的研究不仅应该完善新型的热工具，但也可能建立一种改善的药物方法败血症诱导的多器官衰竭。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NET Formation in Dialysis: A Valuable, albeit Mysterious and Enticing Predictor of Mortality.

DOI：
10.1159/000510772
发表时间：
2020
期刊：
American journal of nephrology
影响因子：
4.2
作者：
Goligorsky MS
通讯作者：
Goligorsky MS

Endothelial Glycocalyx and Cardiomyocyte Damage Is Prevented by Recombinant Syndecan-1 in Acute Myocardial Infarction.

重组 Syndecan-1 可预防急性心肌梗塞中的内皮糖萼和心肌细胞损伤。

DOI：
10.1016/j.ajpath.2022.12.009
发表时间：
2023
期刊：
The American journal of pathology
影响因子：
0
作者：
Vahldieck,Carl;Cianflone,Eleonora;Fels,Benedikt;Löning,Samuel;Depelmann,Patrik;Sabatino,Jolanda;Salerno,Nadia;Karsten,ChristianM;Torella,Daniele;Weil,Joachim;Sun,Dong;Goligorsky,MichaelS;Kusche-Vihrog,Kristina
通讯作者：
Kusche-Vihrog,Kristina

Oscillators in the microvasculature: glycocalyx and beyond.

微脉管系统中的振荡器：糖萼及其他。