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; 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）是一种毁灭性疾病，在前30天内死亡率为50％（30％的患者死于初始出血的影响，10％死于再出血，10％因延迟大脑血管痉挛而死亡）。因此，大多数患者在出血后死于早期脑损伤。 SAH中最重要但未解决的问题之一是脑神经血管损伤，尤其是脑内皮细胞凋亡。内皮细胞凋亡引起血脑屏障（BBB）的破坏导致脑水肿，从而扩大了脑体积以增加颅内压，从而降低了脑血流，从而降低了脑灌注和氧合，并导致额外的缺血性脑损伤。我们来自已建立的大鼠丝穿孔SAH模型的初步数据表明，在SAH后24--72小时内，在24小时内，内皮细胞发生细胞凋亡。如果基础研究能够确定有希望的治疗靶标，那么这个时间课程为临床干预提供了机会窗口。我们的总体假设是SAH通过激活不同的死亡途径并预防脑内皮细胞中的凋亡会减少脑损伤，从而在脑内皮细胞中产生凋亡。在特定的目标1中，我们将研究以下假设：脑内皮凋亡会增强早期脑损伤，这是SAH后高死亡率和发病率的原因。因此，凋亡的时间过程为临床干预打开了机会窗口。在特定的目标2中，我们将研究以下假设：线粒体凋亡途径，尤其是p53和凋亡组（APAF-1-胞染料C-caspase-9） - 依赖性途径，参与内皮凋亡和抑制p53的p53保护BBB完整性并减少早期大脑损伤。在特定的目标3中，我们将研究以下假设：受体凋亡途径，尤其是TNFALPHA，TNFR-1，FADD和CASPASE-8，有助于内皮细胞凋亡和神经血管保护可以预防早期脑损伤。这些临床前研究将继续使用既定的细丝穿孔大鼠SAH模型。我们预计，我们的结果最终将确定凋亡途径的潜在治疗靶标，用于SAH后早期脑损伤的临床治疗。