Glycoproteomics in Ischemic Stroke Related Hyperglycemia

糖蛋白组学在缺血性中风相关高血糖中的应用

• 批准号: 10058002
• 负责人: MINGMING NING
• 金额: $ 46.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058002
• 关键词: Acute; Affect; Alteplase; Biological; Biological Process; Blood; Blood Glucose; Blood Proteins; Blood Vessels; Blood specimen; Brain; Cell Culture Techniques; Clinic; Clinical; Clinical Management; Coagulation Process; Data; Effectiveness; Endothelium; Equilibrium; Exposure to; Extracellular Protein; F8 gene; Fibrinolysis; Functional disorder; Glycoproteins; Homeostasis; Human; Hyperglycemia; Hypoglycemia; Immune response; Impairment; Infarction; Injury; Intravenous; Investigation; Ischemia; Ischemic Stroke; Knowledge; Life; Link; Mass Spectrum Analysis; Mediator of activation protein; Modeling; Molecular and Cellular Biology; Outcome; Oxidation-Reduction; Patients; Pattern; Plasma; Plasminogen Activator Inhibitor 1; Play; Polysaccharides; Post-Translational Protein Processing; Process; Protein Glycosylation; Proteins; Proteomics; Protocols documentation; Publications; Published Comment; Publishing; Role; Signal Pathway; Signal Transduction; Stroke; TFPI; Techniques; Testing; Treatment Efficacy; VWF gene; base; brain endothelial cell; clinical efficacy; clinical predictors; cohort; extracellular; functional outcomes; glycemic control; glycoproteomics; glycosylation; high risk; improved; innovation; ischemic injury; neurovascular injury; novel; novel marker; protein function; protein profiling; response; side effect; stroke patient; stroke therapy; thrombolysis; translational impact

Project Summary/Abstract Acute hyperglycemia is a common clinical problem in ischemic stroke patients, and is frequently associated with impaired thrombolytic efficacy of tPA and predictive of poor functional outcome of stroke patients. However, the clinical management of acute hyperglycemia remains uncertain. Recent studies showed that acute hyperglycemia is associated with rapid alteration in protein glycosylation, which is implicated in a wide range of extracellular signaling pathways and biological functions. It is thus possible that acute hyperglycemia dependent protein glycosylation might play a critical role in regulating thrombolysis and neurovascular injury in stroke patients. We propose to use clinical proteomic approaches to examine protein glycosylation in these patients and then probe mechanism in cell culture. The first aim is to systematically identify changes in blood protein glycosylation associated with acute hyperglycemia in tPA-treated stroke patients using MS-based approach to understand a broad landscape of clinical glyco-protein signals. Then, we validate the results in blood samples of an independent, large cohort of ischemic stroke patients, to select novel biomarkers with high translational impact. Finally, as brain microvascular endothelial cells play a critical role in regulating thrombolysis and blood vessel function via synthesizing and secreting regulatory factors, we aim to examine the glycosylation of proteins secreted by brain endothelial cells under hyperglycemic condition. This may help to understand the role of brain endothelium in regulating extracellular response to ischemic stroke related hyperglycemia. In this resubmission, we have revised extensively according to reviewers’ comments, including adding new experts, new data and publications and experimental details and alternatives.

项目总结/摘要 急性高血糖是缺血性卒中患者常见的临床问题， tPA的溶栓疗效受损，可预测卒中患者的不良功能结局。 然而，急性高血糖症的临床管理仍不确定。最近的研究表明， 急性高血糖症与蛋白质糖基化的快速改变有关，这涉及广泛的 一系列细胞外信号传导途径和生物学功能。因此，急性高血糖症有可能 依赖性蛋白质糖基化可能在调节血栓溶解和神经血管损伤中起关键作用， 中风患者我们建议使用临床蛋白质组学的方法来检查蛋白质糖基化在这些 患者，然后在细胞培养中探索机制。第一个目标是系统地识别血液中的变化 基于MS的tPA治疗的卒中患者中与急性高血糖相关的蛋白糖基化 方法来了解临床糖蛋白信号的广泛景观。然后，我们在 一个独立的，大队列的缺血性中风患者的血液样本，以选择新的生物标志物与高 翻译影响最后，由于脑微血管内皮细胞在调节脑内微循环中起着关键作用， 血栓溶解和血管功能通过合成和分泌调节因子，我们的目的是检查 高血糖状态下脑内皮细胞分泌蛋白的糖基化。这可能有助于 了解脑内皮细胞在缺血性脑卒中相关细胞外反应中的调节作用， 高血糖症在这次重新提交的材料中，我们根据审稿人的意见进行了广泛的修改，包括 增加新的专家、新的数据和出版物以及实验细节和替代品。

项目成果

Effects of aging, hypertension and diabetes on the mouse brain and heart vasculomes.

• DOI: 10.1016/j.nbd.2018.07.021
• 发表时间: 2019-06
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Guo S;Deng W;Xing C;Zhou Y;Ning M;Lo EH
• 通讯作者: Lo EH

Surgical timing in infective endocarditis complicated by intracranial hemorrhage.

感染性心内膜炎并发颅内出血的手术时机。

• DOI: 10.1016/j.ahj.2019.07.011
• 发表时间: 2019
• 期刊: American heart journal
• 影响因子: 4.8
• 作者: Venn,RachaelA;Ning,MingMing;Vlahakes,GusJ;Wasfy,JasonH
• 通讯作者: Wasfy,JasonH

Reperfusion injury after stroke: neurovascular proteases and the blood-brain barrier.

中风后的再灌注损伤：神经血管蛋白酶和血脑屏障。

• DOI: 10.1016/s0072-9752(08)01906-4
• 发表时间: 2009
• 期刊: Handbook of clinical neurology
• 作者: Ning,Mingming;Wang,Xiaoying;Lo,EngH
• 通讯作者: Lo,EngH

The Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score Is Associated With Poor Outcome of Acute Ischemic Stroke.

• DOI: 10.3389/fneur.2020.610318
• 发表时间: 2020
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Tian M;Li Y;Wang X;Tian X;Pei LL;Wang X;Zhang L;Sun W;Wu J;Sun S;Ning M;Buonanno F;Xu Y;Song B
• 通讯作者: Song B

Residual Shunt After Patent Foramen Ovale Closure and Long-Term Stroke Recurrence: A Prospective Cohort Study.

专利孔卵形闭合和长期中风复发后的残留分流：一项前瞻性队列研究。

• DOI: 10.7326/m19-3583
• 发表时间: 2020-06-02
• 期刊: Annals of internal medicine
• 影响因子: 39.2
• 作者: Deng W;Yin S;McMullin D;Inglessis-Azuaje I;Elmariah S;Hung J;Lo EH;Palacios IF;Buonanno FS;Ning M
• 通讯作者: Ning M