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:
- 金额:$ 38.48万
- 依托单位:
- 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:
- 关键词:AffectAlpha GranuleAlteplaseBasic ScienceBindingBlood - brain barrier anatomyBlood PlateletsBlood VesselsCause of DeathCerebral EdemaCerebrumClinicalCoagulation ProcessComplexDataDevelopmentDrug FormulationsFibrinolysisHemorrhageIn VitroIndiumIndividualInjuryIntegrinsInvestigationLDL-Receptor Related Protein 1LesionLipoprotein ReceptorLipoproteinsLow-Density LipoproteinsMediatingMethodsModelingMolecularMorbidity - disease rateMotorMusNecrosisNeurological outcomeOutcomePathogenesisPatientsPeptidesPermeabilityPhysiologicalPlasminogen Activator Inhibitor 1Platelet ActivationPropertyProtease DomainRecombinantsRegulationResidual stateRoleSignal TransductionSiteSudden DeathSurgical ManagementSystemThrombosisTransgenic MiceTransgenic OrganismsTraumatic Brain InjuryVariantVascular PermeabilitiesVasodilationcellular targetingcentral nervous system injurycerebrovascularcognitive functionimprovedin vivoinhibitor/antagonistinsightneuron lossnovelnovel strategiespreventreceptorresearch studythrombolysis
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)仍然是导致死亡和长期发病的主要原因。脑水肿是重型颅脑损伤的常见和不祥的后遗症,它是由于受影响区域的血脑屏障(BBB)完整性丧失和出血引起的。这一应用是基于最近的数据,该数据显示tPA-/-小鼠在脑损伤后相对免受脑水肿和皮质坏死的影响,我们发现tPA直接或间接地增加血脑屏障通透性,方法是通过纤溶外机制诱导血管松弛,涉及通过低密度脂蛋白相关受体(LRP)和整合素avb3的信号转导。在这里,我们建议研究tPA的超纤溶活性如何调节实验性脑外伤的血脑屏障通透性、血管松弛、脑水肿和神经预后。我们的方法包括对tPA介导的信号转导机制的基础研究,使用拮抗剂和tPA变体,通过三个相互关联的特定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血脑屏障通透性和血管松弛的机制。在具体目标2中,将通过分离tPA的纤溶和信号转导活性的方法来阐明血管内血栓形成在创伤后脑损伤发展中的作用。在具体目标3中,将在野生型和tPA-/-小鼠身上检测拮抗剂对在脑外伤后遗症中选择性缺乏纤溶或超纤溶功能的LRP和avb3和tPA变体的影响。此外,一种将tPA输送到创伤血管的新方法将使用表达血小板tPA的转基因小鼠进行评估。总之,这些研究将提供对tPA在介导中枢神经系统损伤中的作用的新的理解,以及可能改善临床结果的新的细胞靶点和新的tPA制剂。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Neuroprotection by glucagon: role of gluconeogenesis.
- DOI:10.3171/2010.4.jns10263
- 发表时间:2011-01-01
- 期刊:
- 影响因子:4.1
- 作者:Fanne, Rami Abu;Nassar, Taher;Higazi, Abd Al-Roof
- 通讯作者:Higazi, Abd Al-Roof
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Abd Alroof HIGAZI其他文献
Abd Alroof HIGAZI的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Abd Alroof HIGAZI', 18)}}的其他基金
Expansion of intracranial hemorrhage by tPA after traumatic brain injury
tPA对脑外伤后颅内出血的扩张作用
- 批准号:
8608015 - 财政年份:2013
- 资助金额:
$ 38.48万 - 项目类别:
Expansion of intracranial hemorrhage by tPA after traumatic brain injury
tPA对脑外伤后颅内出血的扩张作用
- 批准号:
8508346 - 财政年份:2013
- 资助金额:
$ 38.48万 - 项目类别:
相似海外基金
Role of NBEAL2 in alpha granule formation and maturation in megakaryocytes and platelets
NBEAL2 在巨核细胞和血小板中α颗粒形成和成熟中的作用
- 批准号:
462058 - 财政年份:2022
- 资助金额:
$ 38.48万 - 项目类别:
Operating Grants
Molecular Mechanisms of Platelet Alpha Granule Biogenesis
血小板α颗粒生物发生的分子机制
- 批准号:
10528492 - 财政年份:2020
- 资助金额:
$ 38.48万 - 项目类别:
Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
- 批准号:
9884351 - 财政年份:2020
- 资助金额:
$ 38.48万 - 项目类别:
Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
- 批准号:
10656287 - 财政年份:2020
- 资助金额:
$ 38.48万 - 项目类别:
Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
- 批准号:
10161821 - 财政年份:2020
- 资助金额:
$ 38.48万 - 项目类别:
Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
- 批准号:
10434809 - 财政年份:2020
- 资助金额:
$ 38.48万 - 项目类别:
Molecular Mechanisms of Platelet Alpha Granule Biogenesis
血小板α颗粒生物发生的分子机制
- 批准号:
10319019 - 财政年份:2020
- 资助金额:
$ 38.48万 - 项目类别:
Studies of alpha granule formation in human megakaryocytes and platelets
人类巨核细胞和血小板中α颗粒形成的研究
- 批准号:
200126 - 财政年份:2010
- 资助金额:
$ 38.48万 - 项目类别:
Operating Grants
SNARE PROTEINS IN PLATELET ALPHA-GRANULE SECRETION
血小板α颗粒分泌中的诱捕蛋白
- 批准号:
6127440 - 财政年份:2000
- 资助金额:
$ 38.48万 - 项目类别:
SNARE PROTEINS IN PLATELET ALPHA-GRANULE SECRETION
血小板α颗粒分泌中的诱捕蛋白
- 批准号:
6390473 - 财政年份:2000
- 资助金额:
$ 38.48万 - 项目类别: