Proteomic Profiling of Patent Foramen Ovale Related Neurovascular Injury

项目摘要和摘要 卵圆孔未闭(PFO)是右心房和左心房之间的残馀隧道，与 仅在美国，每年就有15万人中风。全氟辛烷磺酸通过允许静脉血栓促进矛盾的栓塞 直接进入大脑。但只有一小部分(10%-17%)的PFO中风患者有已知的倾向 形成静脉血栓：我们建议探索PFO生理学在80-20岁患者血栓前状态中的作用 90%的患者没有已知的高凝状态。由于PFO在普通人群中很常见(25- 30%的成年人)，最近的临床试验排除了80%的高危人群，迫切需要了解 对PFO卒中的发病机制进行更好的个体化治疗。 最初的ESI R01项目假设PFO的生理学可能会产生一种促凝状态。和 采用联合翻译方法，我们检测了血管内PFO前后的心房内血液。 关闭并确定了指示与PFO相关的分流程度的循环因素，这是一个重要的 复发风险标记物。在这次更新中，我们的目标是：1)构建和验证一组生物标记物以测量 基线静脉血中的PFO相关分流状态。该小组将在一个潜在的招募中进行测试 PFO卒中患者的队列，并与超声心动图报告的分流术相比，非PFO卒中患者 控制。2)评估新的与PFO相关的临床危险因素在预测中风复发方面的效果，两者 独立地并与生物标记物面板结合。3)探讨同型半胱氨酸的功能效应 (Hcy)在细胞培养中对人脑内皮细胞的影响。同型半胱氨酸是受PFO关闭影响最大的标记， 与白质疾病和血脑屏障损伤有牵连。它被假设参与到 本研究旨在探讨与PFO分流循环状态相关的多条途径。 在这次重新提交第一次R01更新的过程中，我们对评审员的整体热情和 建设性的意见。我们对这份重新提交的文件进行了广泛的修改，以回应所有审查者的 评论包括：1)为每个目标增加新的详细统计分析和力量分析；2)增加 新的高级生物统计师；3)根据要求提供新的数据；4)重新设计研究以避免选择 偏重于多中心协作计划；5)包括新的非PFO行程控制臂；6)提供 在新出版物中招聘的可行性和方法。 最终，该项目的目标是研究PFO的生理机制，并验证 通过为临床医生提供实用的临床决策，利用新的PFO特定风险因素个性化临床决策 评估个别患者患PFO相关中风或神经血管损伤的风险的手段，如血液测试。

PROJECT SUMMARY AND ABSTRACT Patent foramen ovale (PFO), a residual tunnel between the right and left atria, is associated with more than 150,000 strokes per year in the US alone. PFOs facilitate paradoxical embolism by allowing venous clots to travel directly to the brain. But only a small portion (10-17%) of PFO stroke patients have a known tendency to form venous clots: we propose to explore PFO physiology as a contributor to prothrombotic condition in the 80- 90% of patients without known hypercoagulable state. Since PFOs are common in the general population (25- 30% of adults), and recent clinical trials excluded 80% high risk individuals, there is a dire need to understand the mechanism of PFO stroke better to individualize treatment. The original ESI R01 project hypothesized that the PFO physiology may create a procoagulable condition. And with a combined translational approach we examined intra-atrial blood before and after endovascular PFO closure and have identified circulating factors indicative of the degree of PFO-related shunting, an important recurrent risk marker. In this renewal, we aim to: 1) Construct and validate a panel of biomarkers to measure the PFO-related shunting state from baseline venous blood. The panel will be tested in a prospectively enrolled cohort of PFO stroke patients, and compared to shunting as reported by echocardiogram, with non-PFO stroke controls. 2) Assess the effect of novel PFO-related clinical risk factors in predicting stroke recurrence, both independently and in combination with the biomarker panel. 3) Explore the functional effect of homocysteine (Hcy) on human brain endothelium in cell culture. Hcy is the marker most affected by PFO closure, and has been implicated in white matter disease and blood-brain-barrier injury. It is hypothesized to participate in multiple pathways relevant to the PFO shunting circulatory state which this study aims to explore. In this resubmission for the first R01 renewal, we are deeply grateful for the reviewers’ overall enthusiasm and constructive comments. We have revised this resubmission extensively in response to all the reviewers’ critiques including: 1) addition of new detailed statistical analysis and power analysis for each aim; 2) addition of new senior biostatistician; 3) providing new data as requested; 4) re-designing the study to avoid selection bias with plan for multi-center collaboration; 5) including new non-PFO stroke control arm; 6) providing feasibility of recruitment and methods in new publications. Ultimately, the project aims to investigate mechanisms of PFO physiology and validate markers that individualize clinical decision-making with novel PFO-specific risk factors, by providing clinicians with practical means, such as a blood test, to assess individual patients’ risk of PFO-related stroke or neurovascular injury.