Cell-Specific Targets and Functions of Caspase-9 in Cerebral Ischemia

Caspase-9 在脑缺血中的细胞特异性靶点和功能

基本信息

批准号：
8779777
负责人：
Jennifer Ann Codding-Bui
金额：
$ 1.08万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2014-09-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8779777
关键词：
Address Alteplase Angioneurotic Edema Apoptosis Aspartic Endopeptidases Blood - brain barrier anatomy Blood Vessels Blood flow Brain Caliber Caspase Cause of Death Cell Death Cells Central Nervous System Diseases Cerebral Edema Cerebral Ischemia Cerebrum Cleaved cell Coagulation Process Cysteine Data Development Edema Endothelial Cells Environment Exposure to FDA approved Faculty Family Glucose Human Impairment In Vitro Infarction Inflammation Injury Intervention Ischemia Ischemic Stroke Knock-out Knockout Mice Laboratories Liquid substance Location Measures Mediator of activation protein Mentors Metalloproteases Molecular Mus Neuraxis Neuronal Injury Neurons North America Oxygen Pathogenesis Pathway interactions Play Proteins Pulmonary Edema Regulation Reperfusion Therapy Research Resistance Resources Risk Role Signal Pathway Stroke Stroke prevention Testing Therapeutic Tight Junctions Tissue Inhibitor of Metalloproteinases Tissues Training Programs Traumatic Brain Injury Universities Vascular blood supply Work brain tissue caspase-9 design disability effective therapy in vivo in vivo Model inhibitor/antagonist macular edema mortality neuron loss neuroprotection novel public health relevance therapy development

项目摘要

DESCRIPTION (provided by applicant): A stroke occurs when the blood supply to a portion of the brain is disrupted, depriving brain tissue of oxygen and glucose, and commonly causing cell death. The sole US FDA-approved treatment for ischemic stroke (87 % of all cases), tissue-type plasminogen activator (tPA), dissolves the clot, allowing for reperfusion of the ischemic tissue. However, reperfusion can exacerbate damage to the blood-brain barrier and prompt an abnormal accumulation of fluid in the brain, called edema. Cerebral edema is caused by a loss of vascular integrity of small blood vessels, and is the primary cause of mortality within the firs three days following a stroke. A better understanding of the molecular mechanisms underlying the development of ischemic-induced edema is required for optimal therapeutic treatment. The Troy laboratory has shown that active caspase-9 plays a critical role in the formation of cerebral edema and in neuronal injury. Reversibly inhibiting caspase-9 with a novel, cell-permeant caspase-9 inhibitor provides neuroprotection out to three weeks and abolishes edema in mice. This work proposes a novel mechanism for the development of ischemic induced edema and will utilize in vitro and in vivo approaches to determine caspase-9's role in edema formation. Aim 1 aspires to elucidate the edema-related substrates of caspase-9 to determine the mechanistic details of this medically significant mechanism. Aim 2 seeks to dissect the cell-specific contributions of caspase-9 activation during stroke in endothelial cells and neurons using cell-specific deletion of caspase-9 in mice to identify the location of this mechanism and the order of progression of stroke pathogenesis. This edema-specific mechanism may be broadly applicable to edema in other central nervous system disorders, such as traumatic brain injury and macular edema, and outside the central nervous system in pulmonary edema and angioedema. The intranasal efficacy of this caspase-9 inhibitor affords the potential for developing this therapy a an intervention in human stroke. Columbia University provides an exceptional scientific environment to carry out this research, with high caliber faculty, colleagues, and resources. The training program will provide exposure to seminars, classes in grantsmanship, mentoring opportunities, and interactions with multiple research groups at Columbia and at other universities.

描述（由申请人提供）：当大脑部分的血液供应中断，脑组织缺乏氧气和葡萄糖，通常会导致细胞死亡时，就会发生中风。组织型纤溶酶原激活剂 (tPA) 是美国 FDA 批准的唯一治疗缺血性中风（占所有病例的 87%）的药物，它可以溶解血栓，使缺血组织重新灌注。然而，再灌注会加剧血脑屏障的损伤，并导致大脑中液体异常积聚，称为水肿。脑水肿是由小血管的血管完整性丧失引起的，是中风后三天内死亡的主要原因。为了获得最佳的治疗效果，需要更好地了解缺血性水肿发生的分子机制。 Troy 实验室表明，活性 caspase-9 在脑水肿的形成和神经元损伤中发挥着关键作用。使用新型细胞渗透性 caspase-9 抑制剂可逆地抑制 caspase-9，可提供长达三周的神经保护作用，并消除小鼠水肿。这项工作提出了一种缺血性水肿发生的新机制，并将利用体外和体内方法来确定 caspase-9 在水肿形成中的作用。目标 1 旨在阐明 caspase-9 与水肿相关的底物，以确定这一具有医学意义的机制的机制细节。目标 2 试图利用小鼠体内 caspase-9 的细胞特异性缺失来剖析中风期间内皮细胞和神经元中 caspase-9 激活的细胞特异性贡献，以确定该机制的位置以及中风发病机制的进展顺序。这种水肿特异性机制可能广泛适用于其他中枢神经系统疾病中的水肿，例如创伤性脑损伤和黄斑水肿，以及中枢神经系统外的肺水肿和血管性水肿。这种 caspase-9 抑制剂的鼻内功效为开发这种疗法干预人类中风提供了潜力。哥伦比亚大学为开展这项研究提供了卓越的科学环境，拥有高素质的教师、同事和资源。该培训计划将提供研讨会、资助课程、指导机会以及与哥伦比亚大学和其他大学的多个研究小组的互动。