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: 10599945
• 负责人: MINGMING NING
• 金额: $ 36.75万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599945
• 关键词: Adult; Affect; Anatomy; Aneurysm; Biological Markers; Biology; Blood; Blood - brain barrier anatomy; Blood Tests; Brain; Brain-Derived Neurotrophic Factor; Cell Culture Techniques; Cellular biology; Characteristics; Chronic; Circulation; Clinical; Clinical Trials; Coagulation Process; Collaborations; Critiques; Data; Dose; Drug Metabolic Detoxication; Echocardiography; Embolism; Endothelium; Enrollment; Environmental Risk Factor; Exclusion; Exposure to; Fibroblast Growth Factor; Folic Acid; Functional disorder; Future; Gelatinase B; General Population; Glutamates; Heart; Heart Atrium; Homocysteine; Human; Hyperhomocysteinemia; Injury; Intervention; Knowledge; Left atrial structure; Lung; Mass Spectrum Analysis; Matrix Metalloproteinases; Measurement; Measures; Mediator; Medical; Methods; Modeling; Paradoxical Embolism; Patent Foramen Ovale; Pathway interactions; Patient risk; Patients; Peripheral; Physiological; Physiology; Plasma; Predictive Value; Progress Reports; Protein Isoforms; Proteins; Proteomics; Publications; Published Comment; Recurrence; Reporting; Residual state; Right atrial structure; Risk; Risk Assessment; Risk Factors; Risk Marker; Role; Selection Bias; Serotonin; Signal Transduction; Specificity; Statistical Data Interpretation; Stimulus; Stroke; Syndrome; Taurine; Testing; Thrombophilia; Thrombospondin 1; Time; Toxic effect; Travel; Up-Regulation; Variant; Vascular Endothelium; Venous; White Matter Disease; arm; biomarker panel; biomarker validation; brain endothelial cell; cerebrovascular; clinical decision-making; clinical risk; clinical translation; clinically relevant; cohort; design; diagnosis standard; enhancing factor; extracellular; high risk population; in vivo Model; individual patient; individualized medicine; inhibitor; neurovascular injury; novel; personalized decision; power analysis; prospective; recruit; response; risk stratification; stroke patient; stroke risk; translational approach; vascular injury

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.

项目总结和摘要 卵圆孔未闭（PFO）是左右心房之间的残余隧道， 仅在美国每年就有15万人中风。PFO通过允许静脉凝块 直接进入大脑但只有一小部分（10-17%）的PFO卒中患者有已知的倾向， 形成静脉血凝块：我们建议在80岁以下的老年人中探索PFO生理学作为促血栓形成条件的贡献者。 90%的患者没有已知的高凝状态。由于全氟辛烷磺酸在一般人群中很常见（25- 30%的成年人），最近的临床试验排除了80%的高危人群，因此迫切需要了解 PFO脑卒中的发病机制更好的个体化治疗。 最初的ESI R 01项目假设PFO生理学可能会产生促凝状态。和 采用联合平移方法，我们检查了血管内PFO前后的心房内血液， 关闭，并已确定循环因素的程度指示PFO相关的分流，一个重要的 复发风险标志物。在这次更新中，我们的目标是：1）构建和验证一组生物标志物来测量 与基线静脉血相比，PFO相关的分流状态。将在前瞻性入组的 PFO卒中患者队列，并与超声心动图报告的非PFO卒中分流进行比较 对照2)评估新的PFO相关临床危险因素在预测卒中复发中的作用， 独立地和与生物标志物组组合。3)探讨同型半胱氨酸的功能作用 (Hcy)对人脑内皮细胞的影响Hcy是受PFO关闭影响最大的标志物， 与白色疾病和血脑屏障损伤有关。据推测， 本研究旨在探讨与PFO分流循环状态相关的多种途径。 在第一次R 01更新的重新提交中，我们深深感谢评审员的整体热情， 建设性的意见。我们已经修改了这一重新提交广泛的回应所有审查员的 评论包括：1）为每个目标添加新的详细统计分析和功效分析; 2）添加 新的高级生物统计学家; 3）根据要求提供新数据; 4）重新设计研究以避免选择 多中心协作计划的偏差; 5）包括新的非PFO卒中控制臂; 6）提供 新出版物的征聘和方法的可行性。 最终，该项目旨在研究PFO生理学机制，并验证 通过为临床医生提供实用的 例如血液测试，以评估患者个体发生PFO相关中风或神经血管损伤的风险。

项目成果

May-Thurner syndrome in patients with cryptogenic stroke and patent foramen ovale: an important clinical association.

• DOI: 10.1161/strokeaha.108.527366
• 发表时间: 2009-04
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Kiernan TJ;Yan BP;Cubeddu RJ;Rengifo-Moreno P;Gupta V;Inglessis I;Ning M;Demirjian ZN;Jaff MR;Buonanno FS;Schainfeld RM;Palacios IF
• 通讯作者: Palacios IF

The vasculome of the mouse brain.

• DOI: 10.1371/journal.pone.0052665
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Guo S;Zhou Y;Xing C;Lok J;Som AT;Ning M;Ji X;Lo EH
• 通讯作者: Lo EH

Proteomic Protease Substrate Profiling of tPA Treatment in Acute Ischemic Stroke Patients: A Step Toward Individualizing Thrombolytic Therapy at the Bedside.

• DOI: 10.1007/s12975-010-0047-z
• 发表时间: 2010-12-01
• 期刊: Translational stroke research
• 影响因子: 6.9
• 作者: Ning M;Sarracino DA;Buonanno FS;Krastins B;Chou S;McMullin D;Wang X;Lopez M;Lo EH
• 通讯作者: Lo EH

Patent foramen ovale (PFO), stroke and pregnancy.

• DOI: 10.1136/jim-2016-000103
• 发表时间: 2016-06
• 期刊: Journal of investigative medicine : the official publication of the American Federation for Clinical Research
• 作者: Chen L;Deng W;Palacios I;Inglessis-Azuaje I;McMullin D;Zhou D;Lo EH;Buonanno F;Ning M
• 通讯作者: Ning M

Early elevation of serum tumor necrosis factor-α is associated with poor outcome in subarachnoid hemorrhage.

• DOI: 10.2310/jim.0b013e3182686932
• 发表时间: 2012-10
• 期刊: Journal of investigative medicine : the official publication of the American Federation for Clinical Research
• 作者: Chou SH;Feske SK;Atherton J;Konigsberg RG;De Jager PL;Du R;Ogilvy CS;Lo EH;Ning M
• 通讯作者: Ning M