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Alpha-2-antiplasmin and Ischemic Stroke

Alpha-2-抗纤溶酶和缺血性中风

基本信息

批准号：
9762223
负责人：
Guy L Reed
金额：
$ 37.7万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762223
关键词：
Acute Affect Alteplase Antibodies Antiplasmin Apoptosis Area Blood Vessels Blood coagulation Blood flow Brain Brain Injuries Brain Ischemia Cause of Death Cerebrovascular Circulation Cerebrum Cessation of life Clinical Collaborations Complement Data Deposition Development Disabled Persons Dose Elements Factor XIa Failure Fibrin Fibrinolysis Gelatinase B Genetic Grant Guidelines Health Care Costs Hemorrhage Impairment Infarction Inflammation Inflammatory Inflammatory Response Injury Ischemia Ischemic Brain Injury Ischemic Stroke Kininogenase Lead Link Mediating Minority Modeling Molecular Monoclonal Antibodies National Institute of Neurological Disorders and Stroke Neuronal Injury Neutrophil Infiltration Obstruction Outcome Pathway interactions Patients Perfusion Plasma Plasmin Plasminogen Process Reperfusion Therapy Research Personnel Risk Role Series Serine Protease Serpins Stroke Structure Swelling System Talents Testing Therapeutic Thrombin Thrombosis Thrombus Venous Work adverse outcome base disability effective therapy experimental study improved mutant neurobehavioral neutrophil novel therapeutics perfusion imaging post stroke prevent protective effect public health relevance stroke patient stroke therapy thromboembolic stroke

项目摘要

DESCRIPTION (provided by applicant): As the second leading cause of death and disability, ischemic stroke kills and disables millions of people each year. Tissue plasminogen activator (TPA), the only approved treatment, dissolves the culprit fibrin thrombus to restore blood flow and relieve the brain from ischemia. Unfortunately, after prolonged ischemia, TPA may cause serious or fatal complications; this restricts TPA use to a minority of stroke patients. Although TPA has provided a model for therapeutic fibrinolysis, recent data suggest a new paradigm that assigns a central role to regulatory molecules such as alpha-2-antiplasmin (a2AP) in determining outcomes after ischemic stroke. Clinical observations suggest that high a2AP levels may increase the risk of ischemic stroke and of TPA failure. In experiments that challenge the current therapeutic paradigm for fibrinolytic treatment of stroke, we have shown that a2AP markedly increases brain injury, in a dose-dependent fashion. Conversely, a2AP deficiency or monoclonal antibody inactivation of a2AP, profoundly reduces brain injury, apoptosis, hemorrhage, and swelling. Even after prolonged brain ischemia, a2AP inactivation reduces microvascular thrombosis and MMP-9 expression (a marker of acute inflammation). As a result, a2AP inactivation prevents death and disability after ischemic stroke. Thus, when compared to TPA, a2AP-inactivation appears to provide a safe and effective approach for improving stroke treatment and, through a NINDS collaboration, we are pursuing the development of a2AP inactivation therapy. This proposal seeks to determine the pathophysiologic mechanisms through which a2AP enhances ischemic brain injury after thromboembolic stroke. The organizing hypothesis is that a2AP acts through plasminogen-dependent mechanisms to enhance the development of microvascular thrombosis and impair downstream, microvascular perfusion. Through these mechanisms, a2AP promotes the development of inflammatory responses such as MMP-9 expression and neutrophil recruitment, which have acute deleterious effects. Aim 1 will test the hypothesis that a2AP's deleterious effects in ischemic stroke are due to diminished plasmin(ogen)-dependent, endogenous fibrinolysis that impairs microvascular blood flow through its effect on the culprit thrombus and the development of downstream, thrombin-dependent, microvascular thrombosis. We also propose to examine the hypothesis (Aim 2) that a2AP regulates the endogenous fibrinolytic system to affect the development of ischemic injury, hemorrhage, swelling and survival in thromboembolic stroke through inflammation-linked pathways that require MMP-9 activity and neutrophil deposition. Finally, we will use molecular complementation with specific a2AP mutants to examine the hypothesis that specific structural elements in the a2AP molecule selectively enhance adverse outcomes (such as neuronal injury, hemorrhage, etc.) in ischemic stroke.

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Racial Difference in Symptom Onset to Door Time in ST Elevation Myocardial Infarction.

DOI：
10.1161/jaha.116.003804
发表时间：
2016-09-30
期刊：
Journal of the American Heart Association
影响因子：
5.4
作者：
Bolorunduro O;Smith B;Chumpia M;Valasareddy P;Heckle MR;Khouzam RN;Reed GL;Ibebuogu UN
通讯作者：
Ibebuogu UN

Alpha2-Antiplasmin: The Devil You Don't Know in Cerebrovascular and Cardiovascular Disease.