tPA in traumatic brain injury

tPA在创伤性脑损伤中的作用

• 批准号: 7393150
• 负责人: Abd Alroof HIGAZI
• 金额: $ 38.48万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393150
• 关键词: Affect; Alpha Granule; Alteplase; Basic Science; Binding; Blood - brain barrier anatomy; Blood Platelets; Blood Vessels; Cause of Death; Cerebral Edema; Cerebrum; Clinical; Coagulation Process; Complex; Data; Development; Disruption; Drug Formulations; Fibrinolysis; Hemorrhage; In Vitro; Indium; Individual; Injury; Integrins; Investigation; LDL-Receptor Related Protein 1; Lesion; Lipoprotein Receptor; Lipoproteins; Low-Density Lipoproteins; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Motor; Mus; Necrosis; Neurological outcome; Outcome; Pathogenesis; Patients; Peptides; Permeability; Physiological; Plasminogen Activator Inhibitor 1; Platelet Activation; Property; Protease Domain; Recombinants; Regulation; Residual state; Role; Signal Transduction; Site; Sudden Death; Surgical Management; System; Thinking; Thrombosis; Transgenic Mice; Transgenic Organisms; Traumatic Brain Injury; Variant; Vascular Permeabilities; Vasodilation; cellular targeting; central nervous system injury; cerebrovascular; cognitive function; improved; in vivo; inhibitor/antagonist; insight; neuron loss; novel; novel strategies; prevent; receptor; research study; size; thrombolysis

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) remains a major cause of death and long-term morbidity. Cerebral edema is a common and ominous sequel of severe TBI which results from loss of blood-brain-barrier (BBB) integrity and hemorrhage in the affected zone. This application is predicated on recent data showing that tPA-/- mice are relatively protected from developing cerebral edema and cortical necrosis after TBI and our finding that tPA increases BBB permeability both directly and indirectly by inducing vasorelaxation through extra-fibrinolytic mechanisms that involve signal transduction through the low density lipoprotein related receptor (LRP) and the integrin avb3. Here, we propose to study how the extra-fibrinolytic activities of tPA modulate BBB permeability, vasorelexation, cerebral edema and neurological outcome in experimental TBI. Our approach includes basic research into the mechanism of tPA-mediated signal transduction using antagonists and tPA variants that dissociate its vasoactive and catalytic properties through three inter-related specific aims. In Specific Aim 1 we will study the molecular determinants required to form complexes between avb3 and LRP and mechanism by which tPA disrupts these complexes and induces BBB permeability and vasorelaxation. In Specific Aim 2 the effect of intravascular thrombosis on the development of post-traumatic brain injury will be elucidated using approaches to isolate the fibrinolytic and signal transduction activities of tPA. In Specific Aim 3 the effect of antagonists to LRP and avb3 and tPA variants selectively lacking fibrinolytic or extra-fibrinolytic function in the sequelae of TBI will be examined in wild type and tPA-/- mice. Also, a new approach to deliver tPA to traumatized vessels will be evaluated using platelet-tPA expressing transgenic mice. Together, these studies will provide new understanding of the role of tPA in mediating CNS injury and novel cellular targets and new formulations of tPA that may improve clinical outcome.

描述（由申请人提供）：创伤性脑损伤（TBI）仍然是死亡和长期发病的主要原因。脑水肿是严重 TBI 的常见且不祥的后遗症，是由于血脑屏障 (BBB) 完整性丧失和受影响区域出血造成的。该应用基于最近的数据，显示 tPA-/- 小鼠在 TBI 后相对不会发生脑水肿和皮质坏死，并且我们发现 tPA 通过纤溶外机制诱导血管舒张，直接和间接增加 BBB 通透性，这些机制涉及通过低密度脂蛋白相关受体 (LRP) 和整合素进行信号转导 AVB3。在这里，我们建议研究 tPA 的超纤溶活性如何调节实验性 TBI 中的 BBB 通透性、血管舒张、脑水肿和神经系统结果。我们的方法包括使用拮抗剂和 tPA 变体对 tPA 介导的信号转导机制进行基础研究，这些拮抗剂和 tPA 变体通过三个相互关联的具体目标来分离其血管活性和催化特性。在具体目标 1 中，我们将研究 avb3 和 LRP 之间形成复合物所需的分子决定因素，以及 tPA 破坏这些复合物并诱导 BBB 通透性和血管舒张的机制。在具体目标 2 中，将使用分离 tPA 纤溶和信号转导活性的方法来阐明血管内血栓形成对创伤后脑损伤发展的影响。在具体目标 3 中，将在野生型和 tPA-/- 小鼠中检查 TBI 后遗症中选择性缺乏纤溶或额外纤溶功能的 LRP 和 avb3 和 tPA 变体的拮抗剂的作用。此外，将使用表达血小板 tPA 的转基因小鼠评估一种将 tPA 递送至受伤血管的新方法。总之，这些研究将为 tPA 在介导中枢神经系统损伤中的作用提供新的认识，并提供新的细胞靶点和可改善临床结果的 tPA 新配方。