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: 8956911
• 负责人: Jennifer Ann Codding-Bui
• 金额: $ 4.07万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8956911
• 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（由申请人提供）：当大脑一部分的血液供应被破坏，剥夺脑组织的氧气和葡萄糖，通常导致细胞死亡时，就会发生中风。唯一的FDA批准治疗治疗缺血性中风（所有情况的87％），组织型纤溶酶原激活剂（TPA），溶解了凝块，从而使缺血性组织再灌注。但是，再灌注会加剧对血脑屏障的损害，并促使大脑中液体的异常积累，称为水肿。脑水肿是由小血管的血管完整性丧失引起的，这是中风后三天内FIR的主要原因。对最佳治疗性治疗需要更好地了解缺血性诱发水肿的发展的分子机制。 Troy实验室表明，主动caspase-9在脑水肿的形成和神经元损伤中起关键作用。用一种新型的细胞 - 佩里压caspase-9抑制剂可逆地抑制caspase-9的神经保护剂至三周，并消除小鼠的水肿。这项工作提出了一种新的机制，用于发育缺血性诱导的水肿，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。 AIM 1渴望阐明caspase-9的水肿相关底物，以确定这种具有医学上重要机制的机械细节。 AIM 2试图使用小鼠中caspase-9的细胞特异性缺失在内皮细胞和神经元中caspase-9激活的细胞特异性贡献，以识别该机制的位置以及中风发病机理的进展顺序。这种水肿特异性机制可能广泛地适用于其他中枢神经系统疾病（例如脑损伤和黄斑水肿）以及肺部水肿和血管性水肿的中枢神经系统之外的水肿。该caspase-9抑制剂的鼻内疗效为开发这种疗法的潜力一种干预人类中风。哥伦比亚大学提供了一个卓越的科学环境来进行这项研究，并拥有高素质的教职员工，同事和资源。该培训计划将提供接触研讨会，授予技巧的课程，指导机会以及与哥伦比亚和其他大学的多个研究小组的互动。