Glycocalyx Regeneration to Heal Vascular Inflammation and Atherosclerosis

糖萼再生治愈血管炎症和动脉粥样硬化

基本信息

批准号：
10545041
负责人：
Eno Essien Ebong
金额：
$ 7.85万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-05 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545041
关键词：
Acceleration Adult Affect Aneurysm Anti-Inflammatory Agents Anticoagulants Antiplatelet Drugs Arterial Fatty Streak Arterial Intimas Arteries Aspirin Atherosclerosis Attenuated Binding Blood Vessels Blood flow Cardiovascular Diseases Cardiovascular system Cell Communication Cell Culture Techniques Cell Surface Receptors Cell physiology Cell surface Cells Cellular Infiltration Chemicals Clinical Clinical Treatment Communication Complex Confocal Microscopy Core Protein Coronary Arteriosclerosis Cytoskeleton Data Deposition Dermatan Sulfate Dextrans Diabetes Mellitus Disease Dyes Endothelial Cells Endothelium Environment Enzymes Exhibits Experimental Designs Filtration Formulation Foundations Freeze Substitution Freezing Functional disorder Future Gap Junctions Glycocalyx Glycosaminoglycans Glypican Goals Growth Health Heparitin Sulfate Human Hyaluronan Inflammation Inflammatory Kinetics Left Lipids Liquid substance Low-Density Lipoproteins Mechanics Mediating Medicine Modeling Molecular Morphology Mucous Membrane Myocardial Infarction Myopathy Natural regeneration Nitric Oxide Synthase Patients Pattern Peripheral Vascular Diseases Permeability Pharmaceutical Preparations Phenotype Physiological Play Polysaccharides Psychological reinforcement Publications Regulation Reporting Research Retina Risk Factors Role Severities Shapes Sphingosine-1-Phosphate Receptor Stroke System Testing Therapeutic Thick Translating Transmission Electron Microscopy Vascular Diseases Vascular Permeabilities Visualization Work atherosclerosis risk cell behavior clinical development efficacy testing endothelial dysfunction endothelial regeneration endothelial repair experimental study glucuronyl glucosamine glycan sulfate healing in vivo innovation mechanotransduction monocyte nanomedicine nanoparticle novel novel therapeutic intervention novel therapeutics pre-clinical receptor repaired restoration side effect sphingosine 1-phosphate standard of care sugar syndecan therapy development vascular inflammation

项目摘要

Project Summary: Atherosclerosis – a precursor to coronary artery disease and heart attack, stroke, aneurysm, peripheral vascular disease, and retinal vascular disease – is a condition in which artery walls become eroded, which makes them permeable to inflammatory lipids and cells that form disruptive plaques. Onset of inflammation and atherosclerosis is recognized to coincide with inner blood vessel endothelium shedding of its vasculoprotective glycocalyx coat. The glycocalyx is a sugar-rich layer that lines the inner blood vessel wall and is largely composed of glycosaminoglycans, primarily heparan sulfate (HS) and hyaluronan. Glycocalyx loss disables endothelium function and protection against unwanted molecular and cellular infiltration from the flowing blood. At present, common cardiovascular medicines include lipid lowering and anti-platelet drugs. There is a need for treatments that clinically restore endothelial glycocalyx to treat vascular disease, given that glycocalyx integrity is at the front-line in combating atherosclerosis onset and progression. Recently, there has been new development of therapies to promote glycocalyx health in order to reverse endothelium dysfunction, inflammation, and atherosclerosis. Our research group is contributing to this effort by developing a novel chemical formulation comprised of exogenous mucosal HS and sphingosine-1-phosphate (S1P). We previously reported that this formulation can be used in cell culture experiments to repair degraded endothelial glycocalyx and subsequently to restore transendothelial barrier function (Cheng et al., Int J Nanomedicine, 2016) and interendothelial communication (Mensah et al., PLoS One, 2017). To our knowledge, we are the first group to achieve functional glycocalyx regeneration in cultured endothelial cells. The envisioned project will build upon our previous findings. We intend to further assess feasibility and perform mechanism-of-action studies in endothelial cells cultured in a parallel plate chamber setting in which we can manipulate the fluid and/or chemical environment to model pro-atherosclerotic conditions. This system has commonly been used to test the ability of new drug treatments to mitigate dysfunction and pro-atherosclerotic risk factors in endothelial cells. In Aim 1, we will conjugate, characterize, and optimize the exogenous HS and S1P formulation and test its efficacy and mechanism-of-action in repairing damaged glycocalyx, in the onset of pro-atherosclerotic endothelial dysfunction. Aim 2 will evaluate the ability of glycocalyx reinforcement to attenuate the severity of endothelium hyper-permeability and other endothelial phenotype changes that occur in the early stages of atherosclerosis. This work will lay the foundation for future preclinical in vivo studies and subsequent clinical efforts to further develop the formulation and its utilization.

项目摘要：动脉粥样硬化 - 冠状动脉疾病和心脏病发作，中风，动脉瘤，周围血管疾病和视网膜血管疾病 - 是动脉壁变成的疾病 Eoded，这使它们可以渗透到形成破坏性斑块的炎性脂质和细胞中。发作炎症和动脉粥样硬化被认为与内部血管的植物脱落相吻合血管保护性糖脂外套。糖脂蛋白是一个富含糖的层，在内部血管壁和主要由糖胺聚糖，原发性硫酸盐（HS）和透明质酸组成。糖脂损失禁用内皮功能和防止不需要的分子和细胞浸润。血。目前，常见的心血管药物包括脂质降低和抗血清药物。有一个鉴于糖囊肿，需要在临床上恢复内皮糖脂的治疗以治疗血管疾病完整性在打击动脉粥样硬化的发作和进展方面处于前线。最近，有新的开发促进糖脂健康的疗法以逆转内皮功能障碍，炎症和动脉粥样硬化。我们的研究小组通过开发小说来为这项努力做出贡献化学制定的外源粘膜HS和鞘氨醇1-磷酸（S1P）完成。我们以前报道说，该公式可用于修复降解的内皮糖脂的降解然后恢复跨内皮屏障功能（Cheng等，Int J Nanomedicine，2016年）和间皮间交流（Mensah等人，PLOS One，2017年）。据我们所知，我们是第一个在培养的内皮细胞中实现功能性糖脂再生。设想的项目将基于我们以前的发现。我们打算进一步评估可行性并在内皮细胞在平行板室设置中培养，我们可以操纵流体和/或化学建模促动性条件的环境。该系统通常用于测试新药物治疗可减轻内皮细胞中功能障碍和促成性危险因素。在AIM 1中，我们将共轭，表征和优化外源HS和S1P公式，并测试其有效性和修复受损坏的糖脂的行动机制，在促成骨膜硬化的内皮发作中功能障碍。 AIM 2将评估糖脂加固减轻内皮严重程度的能力在动脉粥样硬化的早期阶段发生过度渗透性和其他内皮表型变化。这项工作将为未来的体内临床前研究和随后的临床努力奠定基础开发公式及其利用。