Neurovascular Protection for Subarachnoid Hemorrhage

蛛网膜下腔出血的神经血管保护

• 批准号: 7243366
• 负责人: John H Zhang
• 金额: $ 35.17万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-07 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7243366
• 关键词: Address; Anesthesiology; Angioplasty; Apoptosis; Apoptotic; Arteries; Basic Science; Blood; Blood - brain barrier anatomy; Brain; Brain Edema; Brain Injuries; Caspase Inhibitor; Cause of Death; Cerebral Aneurysm; Cerebrovascular Circulation; Cerebrovascular Spasm; Cerebrum; Cessation of life; Clinical; Clinical Pathways; Clinical Treatment; Cytochromes; Data; Death Rate; Disease; Disruption; Early treatment; Endothelial Cells; Filament; Functional disorder; Hemorrhage; Hour; Individual; Inflammatory; Inhibition of Apoptosis; Injury; Intervention; Intracranial Hypertension; Ischemic Brain Injury; Longitudinal Studies; MAP Kinase Gene; MAPK14 gene; Mechanics; Mediating; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Nervous System Physiology; Neurologic; Neurons; Operative Surgical Procedures; Pathway interactions; Patients; Perfusion; Prevention; Procedures; Publications; Radiology Specialty; Rate; Rattus; Research; Research Personnel; Rupture; Secure; Spastic; Spontaneous Subarachnoid Hemorrhages; Subarachnoid Hemorrhage; TP53 gene; Techniques; Testing; Time; Week; apoptotic protease-activating factor 1; base; brain volume; caspase-8; caspase-9; cytokine; day; disability; improved; mortality; neurobehavioral; neuron loss; preclinical study; prevent; receptor; therapeutic target

DESCRIPTION (provided by applicant): Subarachnoid hemorrhage (SAH) is a devastating disease carrying with it a mortality of 50% within the first 30 days (30% of patients die from the impact of the initial bleeding, 10% die from re-bleeding and 10% die from delayed cerebral vasospasm). Therefore, most patients die from early brain injury after the impact of bleeding. One of the most important but un-addressed issues in SAH is the early brain neurovascular injury especially cerebral endothelial apoptosis. Endothelial apoptosis initiates blood-brain barrier (BBB) disruption leading to brain edema, which expands brain volume to increase intracranial pressure, thus decreasing cerebral blood flow, impairing cerebral perfusion and oxygenation, and causing additional ischemic brain injury. Our preliminary data from an established rat filament perforate SAH model demonstrates that apoptosis occurs in endothelial cells within 24 hours and in neural cells at 24-72 hours after SAH. This time course provides a window of opportunity for clinical intervention, if basic research can identify promising therapeutic targets. Our overall hypothesis is SAH produces apoptosis in cerebral endothelial cells by activation of distinct death pathways and prevention of apoptosis in cerebral endothelial cells will reduce brain injury. In Specific Aim 1, we will examine the hypothesis that cerebral endothelial apoptosis enhances early brain injury which is responsible for the high mortality and morbidity after SAH; therefore, the time course of apoptosis opens a window of opportunity for clinical intervention. In Specific Aim 2, we will examine the hypothesis that mitochondrial apoptotic pathways, especially p53- and apoptosome (Apaf-1-cytochrome C-caspase-9)- dependent pathways, are involved in endothelial apoptosis and inhibition of p53 protects BBB integrity and reduce early brain injury. In Specific Aim 3, we will examine the hypothesis that receptor apoptotic pathways, especially TNFalpha, TNFR-1, FADD, and caspase-8, contribute to endothelial apoptosis and neurovascular protection will prevent early brain injury. The established filament perforate rat SAH model will continue to be used in these preclinical studies. We expect that our results will ultimately identify potential therapeutic targets of the apoptosis pathway for the clinical treatment of early brain injury after SAH.

描述（由申请人提供）：蛛网膜下腔出血 (SAH) 是一种毁灭性的疾病，在最初的 30 天内死亡率为 50%（30% 的患者死于初次出血的影响，10% 死于再次出血） 10%死于迟发性脑血管痉挛）。因此，大多数患者早期死于脑损伤后出血的影响。 SAH最重要但尚未解决的问题之一是早期脑神经血管损伤，特别是脑内皮细胞凋亡。内皮细胞凋亡引发血脑屏障（BBB）破坏，导致脑水肿，使脑体积扩大，颅内压升高，从而减少脑血流量，损害脑灌注和氧合，引起额外的缺血性脑损伤。我们从已建立的大鼠丝状穿孔SAH模型中得到的初步数据表明，SAH后24小时内内皮细胞发生凋亡，神经细胞发生24-72小时凋亡。如果基础研究能够确定有希望的治疗靶点，那么这个时间过程就为临床干预提供了一个机会之窗。我们的总体假设是 SAH 通过激活不同的死亡途径导致脑内皮细胞凋亡，预防脑内皮细胞凋亡将减少脑损伤。在具体目标 1 中，我们将检验以下假设：脑内皮细胞凋亡会增强早期脑损伤，而早期脑损伤是 SAH 后高死亡率和发病率的原因；因此，细胞凋亡的时间进程为临床干预打开了机会之窗。在具体目标 2 中，我们将检验以下假设：线粒体凋亡途径，尤其是 p53 和凋亡体 (Apaf-1-细胞色素 C-caspase-9) 依赖性途径，参与内皮细胞凋亡，并且抑制 p53 可保护 BBB 完整性并减少内皮细胞凋亡。早期脑损伤。在具体目标 3 中，我们将检验以下假设：受体凋亡途径，尤其是 TNFα、TNFR-1、FADD 和 caspase-8，有助于内皮细胞凋亡，而神经血管保护将预防早期脑损伤。已建立的丝状穿孔大鼠 SAH 模型将继续用于这些临床前研究。我们期望我们的结果最终将确定细胞凋亡途径的潜在治疗靶点，用于 SAH 后早期脑损伤的临床治疗。