NOVEL INHIBITORS OF BRAIN ISCHEMIA

脑缺血的新型抑制剂

• 批准号: 6694156
• 负责人: MICHAEL PETER VITEK
• 金额: $ 28.4万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6694156
• 关键词: behavior test; brain injury; cerebral ischemia /hypoxia; cerebrovascular occlusions; drug screening /evaluation; endopeptidases; enzyme inhibitors; fibrin; laboratory mouse; nonhuman therapy evaluation

DESCRIPTION (provided by applicant): Stroke is a leading cause of death and disability in the United States affecting approximately 750,000 individuals each year. Stroke is characterized by a partial or complete lack of blood flow to a region of the brain that becomes deprived of both oxygen and nutrients and becomes the core of the ischemic, inffacted region. The timely re-establishment of blood flow to ischemic brain by use of thrombolytic agents is a current treatment strategy for acute stroke. The efficacy of this approach, however, is limited by an increased risk for intracerebral hemorrhage (ICH). It was shown that selective inhibition of the intrinsic coagulation pathway, while maintaining the extrinsic coagulation mechanisms, might be efficacious in restoring vascular patency while preventing increased risk for intracerebral hemorrhage. We have previously shown that the recombinant Kunitz proteinase inhibitor (KPI) domain of the amyloid g-protein precursor (APP) is a potent inhibitor of factors XIa and IXa of the intrinsic coagulation pathway, and displays little effect on the extrinsic coagulation pathway and its processes. We propose that the selective inhibitory activity of this KPI domain may be well suited for treatment of acute ischemic brain injury. In Phase I, we will measure the effect of treatment with synthetic KPI domain to reduce fibrin deposition and improve behavioral performance in a mouse model for focal ischemic injury.

描述（由申请人提供）：中风是美国每年影响约75万个人的死亡和残疾的主要原因。中风的特征是部分或完全缺乏流向大脑区域的血流，而大脑区域被剥夺了氧气和养分，并成为缺血性，不足道区域的核心。通过使用溶栓剂及时重新建立了血液流动到缺血性脑的流动是当前急性中风的治疗策略。但是，这种方法的功效受到脑出血（ICH）的风险增加的限制。结果表明，在维持外部凝结机制的同时，选择性抑制内在的凝结途径可能有效地恢复血管通畅，同时防止脑出血的风险增加。我们先前已经表明，淀粉样蛋白G蛋白前体（APP）的重组Kunitz蛋白酶抑制剂（KPI）结构域是内在凝结途径的Xia和IXA的有效抑制剂，并且对外部凝结途径及其过程的影响很小。我们建议该KPI结构域的选择性抑制活性可能非常适合治疗急性缺血性脑损伤。在第一阶段，我们将测量使用合成KPI结构域治疗的效果，以减少纤维蛋白沉积并改善小鼠模型的局灶性缺血性损伤的行为性能。