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

• 批准号: 8880892
• 负责人: Jennifer Ann Codding-Bui
• 金额: $ 2.96万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-14 至 2016-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8880892
• 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

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(申请人提供)：中风发生时，大脑的一部分的血液供应中断，剥夺了脑组织的氧气和葡萄糖，并通常导致细胞死亡。美国FDA批准的唯一治疗缺血性中风的药物(占所有病例的87%)是组织型纤溶酶原激活剂(TPA)，它可以溶解血栓，允许缺血组织的再灌注。然而，再灌流会加剧血脑屏障的破坏，并促使脑内液体异常堆积，称为水肿。脑水肿是由小血管的血管完整性丧失引起的，是中风后头三天内死亡的主要原因。为了达到最佳的治疗效果，需要更好地了解缺血性脑水肿发生的分子机制。特洛伊实验室已经证明，激活的caspase-9在脑水肿的形成和神经元损伤中起着关键作用。用一种新型的细胞特有的caspase-9抑制剂可逆地抑制caspase-9，可以提供长达三周的神经保护，并消除小鼠的水肿。这项工作提出了一种新的缺血性脑水肿的发生机制，并将利用体外和体内方法来确定caspase-9‘S在脑水肿形成中的作用。目的1希望阐明caspase-9与水肿相关的底物，以确定这一医学上重要机制的机制细节。目的2通过对小鼠脑血管内皮细胞和神经元中caspase-9基因的特异性缺失，分析caspase-9在卒中时内皮细胞和神经元中的细胞特异性作用，以确定这一机制的位置和卒中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患的水肿，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水肿。这种caspase-9抑制剂的鼻腔疗效为开发这种治疗方法作为人类中风的干预提供了可能性。哥伦比亚大学为开展这项研究提供了一个特殊的科学环境，拥有高素质的教职员工、同事和资源。培训计划将提供参加研讨会、资助者精神课程、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。