Alpha-2-antiplasmin and Ischemic Stroke

Alpha-2-抗纤溶酶和缺血性中风

• 批准号: 9133478
• 负责人: Guy L Reed
• 金额: $ 37.7万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9133478
• 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; Data; Deposition; Development; Disabled Persons; Dose; Factor XIa; Failure; Fibrin; Fibrinolysis; Gelatinase B; Genetic; Grant; Guidelines; Health; Health Care Costs; Hemorrhage; Image; Indium; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Institutes; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Kininogenase; Lead; Left; 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; Swelling; System; Talents; Testing; Therapeutic; Thrombin; Thrombosis; Thrombus; Venous; Work; adverse outcome; base; disability; effective therapy; improved; killings; mutant; nervous system disorder; neurobehavioral; neutrophil; novel therapeutics; prevent; protective effect; research study; stroke therapy; stroke treatment

 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.

 描述（由申请人提供）： 作为死亡和残疾的第二大主要原因，缺血性中风每年杀死数百万人。唯一经批准的治疗纤维蛋白原激活剂（TPA）溶解了罪魁祸首血栓，以恢复血液流动并从缺血中拯救大脑。不幸的是，在长期缺血之后，TPA可能会引起严重或致命的并发症。这限制了TPA对少数中风患者的使用。尽管TPA为治疗性纤维蛋白溶解提供了一个模型，但最近的数据表明了一种新的范式，该范式在调节分子（例如alpha-2-抗血解剂（A2AP））中分配了核心作用，以确定缺血性中风后的结果。临床观察结果表明，高A2AP水平可能会增加缺血性中风和TPA衰竭的风险。在挑战中风纤维蛋白水解治疗的当前治疗范式的实验中，我们表明A2AP以剂量依赖性方式显着增加了脑损伤。相反，A2AP缺乏或单克隆抗体的A2AP失活，可严重减少脑损伤，凋亡，出血和肿胀。即使在长时间的脑缺血之后，A2AP失活也会降低微血管血栓形成和MMP-9表达（急性炎症的标志）。结果，A2AP失活阻止缺血性中风后死亡和残疾。与TPA相比，A2AP灭活似乎为改善中风治疗提供了一种安全有效的方法，并且通过Ninds协作，我们正在追求A2AP灭活疗法的发展。该建议旨在确定A2AP在血栓性中风后增强缺血性脑损伤的病理生理机制。组织假设是A2AP通过纤溶酶原依赖性机制起作用，以增强微血管血栓形成和损害的发展。下游，微血管灌注。通过这些机制，A2AP促进了具有急性有害作用的炎症反应（例如MMP-9表达和中性粒细胞募集）的发展。 AIM 1将检验以下假设：缺血性中风中A2AP的有害作用是由于纤溶酶（OGEN）依赖性的，内源性纤维蛋白溶解的减少引起的，从而损害了微血管血液对罪魁祸首的作用以及下游依赖于下游的，依赖于凝血酶的微血管，微血管隆布的产生。我们还建议研究A2AP的假设（目标2）调节内源性纤维蛋白水解系统，以影响缺血性损伤，出血，肿胀，肿胀和血栓性中风的生存。最后，我们将使用特定A2AP突变体的分子完成来检查以下假设：A2AP分子中的特定结构元素选择性地增强了缺血性中风中的不良结果（例如神经元损伤，出血等）。