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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.

摘要

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）

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。