Proteomic Profiling of Patent Foramen Ovale Related Neurovascular Injury

卵圆孔未闭相关神经血管损伤的蛋白质组学分析

• 批准号: 7987194
• 负责人: MINGMING NING
• 金额: $ 38.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987194
• 关键词: Acute; Adult; Age; Basic Science; Biology; Blood; Blood Circulation; Blood Platelets; Brain; Brain-Derived Neurotrophic Factor; Cardiac; Cell Culture Techniques; Cellular biology; Cerebrum; Clinical; Clinical Data; Coagulation Process; Consensus; Data; Disease; Down-Regulation; Endothelial Cells; Endothelium; Failure; Feedback; Fibroblast Growth Factor; Filtration; Functional disorder; Gelatinase A; Gelatinase B; General Population; Generations; Heart; Heart Atrium; Human; In Vitro; Injury; Interstitial Collagenase; Isoprostanes; Isotope Labeling; Isotopes; Ketanserin; Left; Left atrial structure; Location; Lung; MEKs; Maps; Matrix Metalloproteinases; Measures; Mediator of activation protein; Modeling; Monitor; Outcome; Oxidative Stress; Paradoxical Embolism; Patent Foramen Ovale; Pathway interactions; Patients; Plasma; Procedures; Proteomics; Recurrence; Reporting; Residual state; Role; Sampling; Screening procedure; Serotonin; Signal Transduction; Specificity; Stroke; Techniques; Technology; Testing; Thrombospondin 1; Time; Travel; U-0126; Up-Regulation; Venous; Western Blotting; base; inhibitor/antagonist; novel; public health relevance; serotonin receptor

DESCRIPTION (provided by applicant): Patent foramen ovale (PFO), a residual tunnel between the right and left atria, is associated with more than 150,000 strokes per year. Traditionally, it was thought that PFOs facilitate paradoxical embolism by allowing venous clots to travel directly to the brain. However, there is a significant disconnect between this simple mechanism and clinical data, as only a small portion (10-17%) of these patients have a known tendency to form clots. Since PFOs are common in the general population (25-30% of adults), the lack of strong clinical consensus on management leaves clinicians with no clear guidance on treatment. We propose a hypothesis of a novel heart-brain signaling mechanism for PFO-related stroke: In the heart: Due to PFO-related right-to-left shunting, serotonin (5-HT) and other unfiltered substances gain direct access to the brain. In the brain: Cerebral endothelium is exposed to elevated 5-HT, and upregulates deleterious neurovascular mediators such as thrombospondin-1(TSP-1), matrix metalloproteinases (MMPs), microparticles (MPs) and more 5-HT, and downregulates neuroprotective signals such as BDNF and FGF. In the circulation: TSP-1 activates platelets, MMPs and microparticles promote endothelial dysfunction, and induce an "acquired" prothrombotic state. Ultimately PFO allows inappropriate signals to avoid filtration by the lungs, staying in the circulation and amplifying each other in a positive feedback loop leading to further neurovascular injury. Our pilot data seem to support our hypothesis and therefore we plan to: 1) characterize neurovascular mediators that are triggered in human cerebral endothelial cell cultures by 5-HT and examine the mechanism of 5-HT-induced neurovascular injury in vitro 2) in the heart, assess acute change in candidate neurovascular mediators in PFO stroke patients before and after PFO closure, and correlate mediators to closure efficacy. 3) explore the longitudinal circulatory proteomic profiles of PFO patients undergoing closure for correlation with clinical outcomes. Clinical endovascular closure of PFO provides a rare opportunity to explore a bedside model to manipulate PFO circulatory signaling. Our combined cell biology and translational clinical approach gives us a unique opportunity to test our novel heart-brain signaling hypothesis in PFO-related stroke. PUBLIC HEALTH RELEVANCE: Since PFO is common in the general population (25-30% of adults) and causes more than 150,000 strokes per year, the lack of understanding of its pathophysiology leaves clinicians with no clear guidance on treatment. Clinical endovascular closure of PFO provides a rare opportunity to explore a bedside model to manipulate PFO circulatory signaling. Our combined cell biology and translational clinical approach gives us a unique opportunity to test our new heart-brain signaling hypothesis in PFO-related stroke.

描述(由申请人提供)：卵圆孔未闭(PFO)是左房和右房之间的残余通道，每年与超过15万次中风有关。传统上，人们认为全氟辛烷磺酸通过允许静脉血栓直接进入大脑而促进矛盾的栓塞。然而，这一简单的机制和临床数据之间存在着显著的脱节，因为这些患者中只有一小部分(10%-17%)有形成血栓的已知倾向。由于PFO在普通人群中很常见(25%-30%的成年人)，缺乏强有力的临床共识，使得临床医生在治疗方面没有明确的指导。我们提出了一种关于PFO相关卒中的新的心脑信号机制的假说：在心脏：由于PFO相关的右向左分流，5-羟色胺(5-HT)和其他未过滤的物质获得了直接进入大脑的途径。脑内：脑内皮细胞暴露于升高的5-羟色胺，上调有害的神经血管介质，如血栓反应素-1(TSP-1)、基质金属蛋白酶(MMPs)、微粒(MPS)和更多的5-羟色胺，下调神经保护信号，如BDNF和FGF。在循环中：TSP-1激活血小板，MMPs和微粒促进内皮功能障碍，并诱导“获得性”血栓前状态。最终，PFO允许不适当的信号避开肺部的过滤，停留在循环中，并在正反馈循环中相互放大，从而导致进一步的神经血管损伤。我们的初步数据似乎支持我们的假设，因此我们计划：1)表征5-羟色胺在人脑内皮细胞培养中触发的神经血管介质的特征，并研究5-羟色胺在体外诱导的心脏神经血管损伤的机制；2)在心脏中，评估PFO卒中患者关闭PFO前后候选神经血管介质的急性变化，并将介质与关闭效果相关联。3)探讨封堵术中PFO患者的纵向循环蛋白质组学特征及其与临床预后的关系。临床血管内封堵术为探索控制PFO循环信号的床边模型提供了难得的机会。我们的细胞生物学和翻译临床相结合的方法为我们提供了一个独特的机会来测试我们在PFO相关中风中的新的心脏-大脑信号转导假说。 公共卫生相关性：由于PFO在普通人群(25%-30%的成年人)中很常见，每年导致超过15万人中风，对其病理生理学缺乏了解，使得临床医生对治疗没有明确的指导。临床血管内封堵术为探索控制PFO循环信号的床边模型提供了难得的机会。我们的细胞生物学和转译临床相结合的方法为我们提供了一个独特的机会来测试我们在PFO相关中风中的新的心脏-大脑信号假说。