tPA in traumatic brain injury

tPA在创伤性脑损伤中的作用

基本信息

批准号：
7603049
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
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7603049
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 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 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 thrombolysis

项目摘要

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率的主要原因。脑水肿是严重TBI的常见和不祥的续集，它是由于受影响区域中血脑屏障（BBB）完整性和出血的丧失而导致的。该应用是基于最近的数据，表明TPA - / - 小鼠受到TBI后的脑水肿和皮质坏死的发展，并且我们的发现，TPA通过通过涉及低dip依赖于信号的lip依赖于低调的机制来直接和间接地增加BBB的渗透性，从而直接和间接地诱导BBB的渗透性。 AVB3。在这里，我们建议研究TPA的纤维蛋白分解活性如何调节BBB的渗透率，血管甲状腺素化，脑水肿和实验性TBI的神经系统结果。我们的方法包括使用拮抗剂和TPA变体对TPA介导的信号转导机理的基础研究，这些变体通过三个相关的特定目的通过三个相互关联的特定目的来解离其血管活性和催化性能。在特定目标1中，我们将研究在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渗透性和血管延迟的机制。在特定的目标2中，使用方法揭示了血管内血栓形成对创伤后脑损伤发展的影响，将使用隔离TPA的纤维蛋白水解和信号转导活性的方法来阐明。在特定目标3中，将在野生型和TPA - / - 小鼠中检查拮抗剂对LRP和AVB3和TPA变体的影响，在TBI后遗症中缺乏纤维蛋白水解或纤维蛋白分解功能。同样，将使用表达转基因小鼠的血小板-TPA评估一种将TPA传递给创伤血管的新方法。总之，这些研究将为TPA在中介中枢神经系统损伤和新型细胞靶标和TPA的新配方中的作用提供新的了解，从而可以改善临床结果。