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：
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
项目类别：
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

项目摘要

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.

项目摘要和摘要专利孔卵形（PFO）是左右心房之间的残留隧道 150,000笔perys peres peres peres peres peres。直接前往大脑，但只有一小部分（10-17％）中风患者有已知的趋势。形成静脉血块：我们建议探索PFO生理学，作为80-的促血栓形成状况的贡献者由于PFO在普通人群中，有90％的患者患有已知的高凝状态（25-- 30％的成年人），最近的临床不包括80％的高风险个人，这是一个可怕的需要理解的 PFO中训练的机制可以更好地个性化治疗。原始的ESI R01项目假设PFO生理可能会产生可启动的状态与转化的转化后的作者内蓝色和铅血管内PFO之后闭合并确定了循环循环因子，指示与PFO相关的分流程度，这是一个重要的经常性风险标记。基线静脉血液中与PFO相关的分流状态。 PFO中风患者的队列，并与超声心动图造影术相比，与非PFO中风相比控制。无与伦比并与生物标志物组合组合。（HCY）在细胞培养中的人脑森植物上。与白质疾病和血液恶有关。与PFO驱动循环状态相关的多个途径，该循环状态旨在探索。在此重新提交第一个R01续订时，我们非常感谢审稿人的整体热情和建设性的评论。批评包括：1）为每个目标增加新的详细统计分析和功率分析；根据要求提供新数据的新高级生物群体；与中央协作的偏见； 5）提供了新的非PFO中风控制臂；新出版物中招聘和方法的盛宴。最终，该项目旨在调查PFO生理的机制，并验证标记通过为临床医生提供实用诸如血液测试之类的手段，以评估个别患者患PFO相关的中风或神经血管损伤的风险。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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
影响因子：
0
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
影响因子：
0
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

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