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、中风、动脉瘤、周围血管疾病和视网膜血管疾病——是动脉壁变质的一种病症侵蚀，这使得它们能够渗透到形成破坏性斑块的炎症脂质和细胞。炎症和动脉粥样硬化被认为与其内血管内皮脱落同时发生。血管保护性糖萼层糖萼是一层富含糖的层，排列在血管内壁和血管壁上。主要由糖胺聚糖组成，主要是硫酸乙酰肝素 (HS) 和糖萼损失。禁用内皮功能并防止流动的不需要的分子和细胞渗透目前常见的心血管药物有降脂药和抗血小板药。鉴于糖萼，临床上需要恢复内皮糖萼的治疗方法来治疗血管疾病完整性是对抗动脉粥样硬化发生和进展的最前线。最近出现了新的情况。开发促进糖萼健康的疗法，以逆转内皮功能障碍，我们的研究小组正在开发一种新型药物，为这一努力做出贡献。化学制剂由外源性粘膜 HS 和 1-磷酸鞘氨醇 (S1P) 组成。报道称，该制剂可用于细胞培养实验，修复降解的内皮糖萼随后恢复跨内皮屏障功能（Cheng 等人，Int J Nanomedicine，2016）和内皮间通讯（Mensah et al., PLoS One, 2017）。在培养的内皮细胞中实现功能性糖萼再生。我们打算进一步评估可行性并进行作用机制研究。在平行板室环境中培养的内皮细胞，我们可以在其中操纵流体和/或化学物质该系统通常用于测试促动脉粥样硬化的能力。减轻内皮细胞功能障碍和促动脉粥样硬化危险因素的新药物治疗。我们将缀合、表征和优化外源 HS 和 S1P 制剂，并测试其功效和在促动脉粥样硬化内皮细胞发生过程中修复受损糖萼的作用机制目标 2 将评估糖萼强化减轻内皮严重程度的能力。动脉粥样硬化早期发生的高渗透性和其他内皮表型变化。这项工作将为未来的临床前体内研究和后续临床工作进一步奠定基础。开发配方及其应用。