Ac-SDKP for Treatment of Acute Stroke

Ac-SDKP 治疗急性中风

基本信息

批准号：
8504109
负责人：
ZHENG GANG ZHANG
金额：
$ 32.48万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8504109
关键词：
Adverse effects Aftercare Alteplase Animals Astrocytes Blood - brain barrier anatomy Blood Vessels Brain hemorrhage Cause of Death Cerebral Ischemia Cerebral hemisphere hemorrhage Cerebrospinal Fluid Cerebrum Clinical Trials Combined Modality Therapy Complication Confocal Microscopy Data Development Dose Down-Regulation Elderly Endothelial Cells Extravasation Failure Fright Human Incidence Infarction Ischemia Lasers Light Magnetic Resonance Imaging Measures Middle Cerebral Artery Occlusion Modeling Molecular Neurological outcome Neurons Nuclear Pathway interactions Patients Peptides Perfusion Pharmaceutical Preparations Plasma Plasminogen Activator Rattus Reperfusion Therapy Risk Signal Pathway Stroke Testing Therapeutic Thrombosis Time Tissues Transforming Growth Factors United States Food and Drug Administration acute stroke aged disability effective therapy goralatide improved neuron loss neurovascular unit neutralizing monoclonal antibodies novel public health relevance response thrombolysis transcription factor young adult

项目摘要

DESCRIPTION (provided by applicant): Stroke is a leading cause of death and disability worldwide and approximately 72% of people who suffer a stroke are over the age of 65. Tissue plasminogen activator (tPA) is the only drug approved by the Food and Drug Administration (FDA) for treatment of acute stroke (within 4.5h). The most feared complication after tPA treatment of stroke is an increased risk of cerebral hemorrhage. Our preliminary data indicate that N-acetyl- seryl-aspartyl-lysyl-proline (Ac-SDKP), a peptide normally presented in human plasma, in combination with tPA reduced infarct volume by more than 50% and improved neurological outcome, but did not increase the incidence of hemorrhagic transformation in young adult rats. In this application, we propose to develop a combination therapy of Ac-SDKP and tPA for treatment of acute stroke in aged rats and to investigate molecular mechanisms underlying the combination therapy on the neurovascular unit. In Specific Aim 1, using MRI and 3D laser confocal microscopy, we will investigate the effect of Ac-SDKP alone and Ac-SDKP in combination with tPA on recanalization of the occluded MCA, cerebral microvascular perfusion and vascular integrity, brain hemorrhage, and ischemic neuronal damage in aged rats subjected to embolic middle cerebral artery occlusion (MCAO). In Specific Aim 2, we will examine whether Ac-SDKP suppresses the ischemia- and tPA-activated nuclear transcription factor-?B (NF-?B) pathway in cerebral vessels, which leads to enhancement of cerebral microvascular patency and integrity by reduction of thrombosis. In Specific Aim 3, we will examine whether Ac-SDKP blocks the ischemia- and tPA-activated transforming growth factor ¿ (TGF¿) signaling pathway in cerebral vessels and astrocytes, which leads to reduction of thrombosis by downregulation of plasminogen activator inhibitor1 (PAI-1). These studies could potentially provide a new therapy to minimize the adverse effect of tPA on ischemic neurovascular damage, leading to improved neurological outcomes after acute stroke.

描述（由申请人提供）：中风是全世界死亡和残疾的主要原因，大约 72% 的中风患者年龄在 65 岁以上。组织纤溶酶原激活剂 (tPA) 是美国食品药品监督管理局批准的唯一药物治疗急性中风（4.5 小时内）的给药 (FDA) 我们的初步数据表明，tPA 治疗中风后最令人担心的并发症是脑出血的风险增加。 N-乙酰基-丝氨酰-天冬氨酰-赖氨酰-脯氨酸 (Ac-SDKP) 是一种通常存在于人血浆中的肽，与 tPA 联合使用可将梗塞体积减少 50% 以上，并改善神经系统结果，但不会增加出血的发生率在本申请中，我们建议开发 Ac-SDKP 和 tPA 的联合疗法来治疗老年大鼠的急性中风，并研究联合疗法对神经血管的分子机制。在具体目标 1 中，我们将使用 MRI 和 3D 激光共聚焦显微镜，研究 Ac-SDKP 单独使用以及 Ac-SDKP 与 tPA 联合使用对闭塞 MCA 的再通、脑微血管灌注和血管完整性、脑出血、在特定目标 2 中，我们将检查 Ac-SDKP 是否会影响大脑中动脉栓塞 (MCAO) 的老年大鼠的缺血性神经元损伤。抑制脑血管中缺血和 tPA 激活的核转录因子 -βB (NF-βB) 通路，从而通过减少血栓形成来增强脑微血管的通畅性和完整性。 -SDKP 阻断缺血和 tPA 激活的转化生长因子 ¿ (TGF¿) 脑血管和星形胶质细胞中的信号通路，通过下调纤溶酶原激活剂抑制剂 1 (PAI-1) 减少血栓形成。这些研究可能提供一种新的疗法，以尽量减少 tPA 对缺血性神经血管损伤的不利影响。改善急性中风后的神经系统结果。