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: 8679015
• 负责人: MINGMING NING
• 金额: $ 37.56万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679015
• 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; endothelial dysfunction; inhibitor/antagonist; novel; 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）：每年左右心房之间的残留隧道，卵子孔（PFO）专利孔（PFO）与每年超过150,000笔相关。传统上，人们认为，PFO通过允许静脉血块直接进入大脑来促进矛盾的栓塞。但是，这种简单的机制和临床数据之间存在明显的断开连接，因为这些患者中只有一小部分（10-17％）具有已知的凝块趋势。由于PFO在普通人群中很常见（占成年人的25-30％），因此缺乏对管理的临床医生缺乏强烈的临床共识，这使临床医生没有明确的治疗指导。我们提出了与PFO相关的中风的新型心脑信号传导机制的假设：在心脏：由于PFO相关的右至左分类，5-羟色胺（5-HT）和其他未过滤的物质可以直接进入大脑。 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.在循环中：TSP-1激活血小板，MMP和微粒会促进内皮功能障碍，并诱导“获得的”原肿性状态。最终，PFO允许不适当的信号避免肺部过滤，留在循环中，并以积极的反馈回路相互扩增，从而导致进一步的神经血管损伤。我们的试验数据似乎支持我们的假设，因此我们计划：1）表征通过5-HT在人脑大脑内皮细胞培养中触发的神经血管介质的特征，并检查了5-HT诱导的神经血管损伤的机制，体外2）在心脏中评估急性神经血管中的Mediator及其在PFO且PFO STROKE的急性变化的PFO STROKE，并在PFO STROKE中的急性变化。关闭功效。 3）探索闭嘴的PFO患者的纵向循环蛋白质组织特征与临床结局相关。 PFO的临床血管内闭合提供了一个难得的机会来探索床头模型来操纵PFO循环信号传导。我们组合的细胞生物学和翻译临床方法为我们提供了一个独特的机会，可以测试与PFO相关的中风中新颖的心脑信号假设。