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

• 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
• 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

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.

项目概述：动脉粥样硬化-冠状动脉疾病和心脏病发作，中风， 动脉瘤、外周血管疾病和视网膜血管疾病-是一种动脉壁变得 这使得它们可以渗透到形成破坏性斑块的炎症脂质和细胞中。发作 炎症和动脉粥样硬化被认为是与内血管内皮脱落相一致的， 保护血管的糖萼衣。糖萼是一种富含糖的层，排列在血管内壁上， 主要由糖胺聚糖组成，主要是硫酸乙酰肝素（HS）和透明质酸。糖萼丧失 使内皮功能丧失， 血目前常用的心血管药物包括降脂药和抗血小板药。有一个 需要临床上恢复内皮糖萼以治疗血管疾病的治疗， 完整性是对抗动脉粥样硬化发作和进展的第一线。最近，有新的 开发促进糖萼健康的疗法以逆转内皮功能障碍， 炎症和动脉粥样硬化。我们的研究小组正在通过开发一种新的 由外源性粘膜HS和鞘氨醇-1-磷酸（S1 P）组成的化学制剂。我们之前 报道，该制剂可用于细胞培养实验，以修复降解的内皮糖萼 并随后恢复跨内皮屏障功能（Cheng等，Int J Nanomedicine，2016）和 内皮间通讯（Mensah等，PLoS One，2017）。据我们所知，我们是第一批 在培养的内皮细胞中实现功能性糖萼再生。设想的项目将建立在 我们之前的发现我们打算进一步评估可行性，并进行作用机制研究， 内皮细胞培养在平行板室设置，其中我们可以操纵流体和/或化学物质， 环境来模拟促动脉粥样硬化状况。该系统通常用于测试 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治疗。在目标1中， 我们将结合、表征和优化外源性HS和S1 P制剂，并测试其功效， 修复受损糖萼的作用机制，在促动脉粥样硬化内皮 功能障碍目的2评价糖萼强化减轻内皮损伤的能力 动脉粥样硬化早期出现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的临床工作奠定基础，以进一步 开发配方和应用。