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: 8496882
• 负责人: MINGMING NING
• 金额: $ 36.62万
• 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/8496882
• 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; 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; Right atrial structure; Role; Sampling; 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; receptor; screening

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.

描述（由申请人提供）：卵圆孔未闭（PFO）是左右心房之间的残留通道，每年与超过150,000例中风有关。传统上，人们认为全氟辛烷磺酸通过允许静脉凝块直接移动到大脑而促进矛盾栓塞。然而，这种简单的机制与临床数据之间存在明显的脱节，因为只有一小部分（10-17%）的患者具有已知的血栓形成倾向。由于PFOs在一般人群中很常见（占成年人的25-30%），因此缺乏强有力的临床共识，导致临床医生没有明确的治疗指导。我们提出了pfo相关中风的一种新的心脑信号传导机制的假设：在心脏中：由于pfo相关的右至左分流，5-羟色胺（5-HT）和其他未经过滤的物质直接进入大脑。在大脑中：脑内皮暴露于升高的5-HT，并上调有害的神经血管介质，如血栓反应蛋白-1(TSP-1)，基质金属蛋白酶（MMPs），微粒（MPs）和更多的5-HT，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，诱导“获得性”血栓形成前状态。最终，PFO允许不适当的信号避免被肺部过滤，留在循环中，并在一个正反馈回路中相互放大，导致进一步的神经血管损伤。我们的试点数据似乎支持我们的假设，因此我们计划：1)表征5-HT在人脑内皮细胞培养中触发的神经血管介质，并检查5-HT诱导的体外神经血管损伤机制2)在心脏中，评估PFO卒中患者在PFO关闭前后候选神经血管介质的急性变化，并将介质与关闭效果联系起来。3)探讨PFO闭合患者的纵向循环蛋白质组学特征与临床预后的相关性。PFO的临床血管内闭合为探索床边模型来控制PFO循环信号提供了难得的机会。我们结合细胞生物学和转化临床方法为我们提供了一个独特的机会来测试我们在pfo相关中风中新颖的心脑信号传导假说。