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

基本信息

批准号：
8287075
负责人：
MINGMING NING
金额：
$ 37.94万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/8287075
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 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 receptor

项目摘要

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) 是左右心房之间的残余通道，每年与超过 150,000 次中风相关。传统上，人们认为 PFO 允许静脉血栓直接流向大脑，从而促进矛盾栓塞。然而，这种简单的机制与临床数据之间存在显着的脱节，因为这些患者中只有一小部分（10-17%）已知有形成血栓的倾向。由于 PFO 在普通人群（25-30% 的成年人）中很常见，因此在治疗方面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。我们提出了一种针对 PFO 相关中风的新型心脑信号传导机制的假设：在心脏中：由于 PFO 相关的从右向左分流，血清素 (5-HT) 和其他未经过滤的物质可以直接进入大脑。在大脑中：脑内皮暴露于升高的 5-HT 中，上调有害的神经血管介质，如血小板反应蛋白-1 (TSP-1)、基质金属蛋白酶 (MMP)、微粒 (MP) 和更多 5-HT，并下调神经保护信号例如 BDNF 和 FGF。在循环中：TSP-1 激活血小板、MMP 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免被肺部过滤，留在循环中并在正反馈循环中相互放大，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) 表征在人脑内皮细胞培养物中由 5-HT 触发的神经血管介质，并在体外检查 5-HT 诱导的神经血管损伤的机制 2) 在心脏，评估 PFO 中风患者在 PFO 闭合前后候选神经血管介质的急性变化，并将介质与闭合效果相关联。 3) 探索接受封堵术的 PFO 患者的纵向循环蛋白质组学特征与临床结果的相关性。 PFO 的临床血管内封堵为探索操纵 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化临床方法相结合，为我们提供了一个独特的机会来测试我们在 PFO 相关中风中的新型心脑信号传导假说。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，每年会导致超过 150,000 例中风，因此对其病理生理学缺乏了解，导致临床医生无法获得明确的治疗指导。 PFO 的临床血管内封堵为探索操纵 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化临床方法相结合，为我们提供了一个独特的机会来测试 PFO 相关中风的新心脑信号假说。