The glycocalyx: a potential contributor to post-stroke complications

糖萼：中风后并发症的潜在因素

• 批准号: 2454265
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2454265
• 关键词: glycocalyx; potential; contributor; post; stroke

Stroke remains a leading cause of death and disability worldwide with limited treatment options. In addition to the immediate and common symptoms of stroke such as limb weakness and speech problems, stroke patients often develop complications. These complications include infection, which can develop quickly, or those that develop over time including anxiety, depression, fatigue, and memory impairment. These problems have a negative impact on recovery and quality of life after stroke. Most stroke patients are elderly and/or present with co-morbidity (such as recent infection, hypertension, diabetes or obesity); conditions or risk factors that can affect outcome and recovery. Our previous work has tried to better model a typical stroke patient by including co-morbidity and has shown that outcome after experimental stroke is worse in the presence of co-morbidities like obesity. An important factor in the response to stroke is the health of the cerebrovasculature. Most risk factors for stroke cause a perturbation in the vascular system that affects structure and function. Understanding the changes in vasculature after stroke is therefore key to successful targeting of mechanisms that lead to worse outcome. One unappreciated component of the vasculature is the glycocalyx. The glycocalyx is a layer comprised of proteoglycans, glycosaminoglycan chains, and glycoproteins that covers the luminal surface of endothelial cells and has an important role in maintaining vascular health. Functions of the glycocalyx include limiting vascular permeability, leukocyte adhesion and microvascular thrombosis and control of microvascular tone. Reduced glycocalyx thickness is seen in hypertension, diabetes and obesity. In stroke patients the glycocalyx is also thinner and an increase in its soluble components in the plasma have been observed, suggesting sheddase activity and glycocalyx damage. Furthermore, cognitive impairment after sepsis is thought to be mediated by glycocalyx shedding. Thus, we hypothesise that glycocalyx shedding in the cerebrovasculature after stroke could impair vascular function and worsen outcome. Specifically, the student will use an experimental model of stroke to test if glycocalyx breakdown causes/increases short-term and long-term (memory impairment, anxiety, depression and fatigue) complications after stroke. The student will also determine the impact of the co-morbidity obesity. Finally, the student will test if breakdown products of the glycoclayx can be detected in the blood of stroke patients and if they are linked to a higher risk of development of longer-term post-stoke complications including memory decline, depression and fatigue. This study will provide essential data indicating whether glycocalyx breakdown affects the risk of post-stroke complications, and this may lead to a new avenue for therapeutic intervention to improve recovery after stroke.

中风仍然是全球死亡和残疾的主要原因，治疗选择有限。除了肢体无力和言语问题等中风的即时和常见症状外，中风患者还经常出现并发症。这些并发症包括感染，可以迅速发展，或随着时间的推移，包括焦虑，抑郁，疲劳和记忆障碍。这些问题对中风后的恢复和生活质量有负面影响。大多数卒中患者为老年人和/或存在合并症（如近期感染、高血压、糖尿病或肥胖）;可能影响结局和恢复的疾病或风险因素。我们以前的工作试图通过包括共病来更好地模拟典型的中风患者，并且已经表明实验性中风后的结果在存在肥胖等共病的情况下更糟。中风反应的一个重要因素是脑血管系统的健康。中风的大多数危险因素引起血管系统的扰动，影响结构和功能。因此，了解卒中后血管系统的变化是成功靶向导致更差结局的机制的关键。糖萼是脉管系统中一个未被重视的组成部分。糖萼是由蛋白聚糖、糖胺聚糖链和糖蛋白组成的层，其覆盖内皮细胞的腔表面，并且在维持血管健康中具有重要作用。糖萼的功能包括限制血管通透性、白细胞粘附和微血管血栓形成以及控制微血管张力。糖萼厚度减少见于高血压、糖尿病和肥胖症。在中风患者中，糖萼也变薄，并且已经观察到其血浆中可溶性组分的增加，表明脱落酶活性和糖萼损伤。此外，脓毒症后的认知障碍被认为是由糖萼脱落介导的。因此，我们假设卒中后脑血管系统中的糖萼脱落可能损害血管功能并使预后恶化。具体来说，学生将使用中风的实验模型来测试糖萼分解是否会导致/增加中风后的短期和长期（记忆障碍，焦虑，抑郁和疲劳）并发症。学生还将确定共病肥胖的影响。最后，学生将测试是否可以在中风患者的血液中检测到glycoclayx的分解产物，以及它们是否与中风后长期并发症（包括记忆力下降，抑郁和疲劳）的发展风险较高有关。这项研究将提供必要的数据，表明糖萼分解是否会影响中风后并发症的风险，这可能会为改善中风后恢复的治疗干预开辟一条新途径。