Neurovascular protection by adropin in acute neural injury from subarachnoid hemorrhage

阿德罗平对蛛网膜下腔出血急性神经损伤的神经血管保护作用

• 批准号: 10682458
• 负责人: Brian Lim Hoh
• 金额: $ 37.95万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682458
• 关键词: Acute; Adhesions; Astrocytes; Autologous; Basic Science; Binding Proteins; Biological Assay; Biological Availability; Blood; Blood Platelets; Brain; Brain Injuries; C57BL/6 Mouse; Cerebral Edema; Cerebral Infarction; Cerebrovascular Circulation; Cerebrovascular Spasm; Cerebrum; Cessation of life; Clinical Trials; Cognitive deficits; Data; Development; Endothelial Cells; Endothelium; Erythrocytes; Florida; Foundations; Functional disorder; Gene Expression; Goals; Hemoglobin; Hemorrhage; Hour; Human; In Vitro; Infarction; Injections; Injury; Intraventricular; Ischemia; Knock-out; Knockout Mice; Knowledge; Magnesium Sulfate; Mediating; Mediator; Meta-Analysis; Mission; Modeling; Molecular; Mus; NOS3 gene; National Institute of Neurological Disorders and Stroke; Nimodipine; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Signaling Pathway; Nitric Oxide Synthetase Inhibitor; Nitrogen; Nucleic Acid Regulatory Sequences; Oral; Outcome; Oxidative Stress; PPAR alpha; Pathway interactions; Patients; Peptides; Pericytes; Permeability; Phase; Phosphorylation; Placebos; Production; Public Health; Reactive Oxygen Species; Regulation; Reporter; Research; Research Personnel; Role; Simvastatin; Subarachnoid Hemorrhage; Surgical Clips; Therapeutic; Thrombosis; Tight Junctions; Transgenes; Transgenic Mice; Uncertainty; Universities; Vasodilation; Vasospasm; antagonist; beta Actin; brain endothelial cell; chromatin immunoprecipitation; clinical translation; disability; experimental study; improved; inhibitor; monolayer; nerve injury; nervous system disorder; neurobehavioral; neurological recovery; neuron apoptosis; neuroprotection; neurovascular; novel; novel therapeutic intervention; overexpression; peptide hormone; pre-clinical; preservation; prevent; prophylactic; protective effect; protein expression; radiological imaging; randomized trial; response; therapeutic target; transcriptome sequencing

ABSTRACT Acute neural injury from subarachnoid hemorrhage (SAH)-associated cerebral infarction occurs in 30-40% of patients who survive the initial hemorrhage, leads to death and disability, and most strongly correlates with 3- month outcome. There is also a significant rate of long-term cognitive deficits. Current understanding of the pathophysiology of post-SAH cerebral infarction points to injury cascades involving decreased nitric oxide (NO) bioavailability and oxidative stress. Under normal conditions, NO signaling pathways regulate cerebral blood flow by mediating cerebral vasodilation and inhibiting platelet adhesion. However, with SAH, red blood cells lyse and release hemoglobin, which is a spasmogenic. Hemoglobin scavenges NO; stimulates production of a nitric oxide synthase (NOS) inhibitor (ADMA); and generates reactive oxygen species (ROS) and nitrogen species (RNS). We believe the recently-identified peptide hormone adropin is a promising therapeutic target for post-SAH cerebral infarction. Our group and others have shown adropin is abundantly expressed in the brain, regulates the endothelial nitric oxide synthase (eNOS) pathway, correlates with markers of oxidative stress, and reduces brain endothelial permeability in response to simulated ischemia. Our hypothesis is that adropin confers protection against acute neural injury from post-SAH cerebral infarction. Our overall goal in this proposal is to demonstrate the protective role of adropin in SAH and investigate the underlying molecular and cellular mechanisms of this protection. Our preliminary data support this hypothesis by showing that SAH decreases brain adropin expression, and that endogenous adropin overexpression by transgenic mice with a β-actin-driven adropin transgene (AdrTg) or treatment with synthetic adropin in the SAH model reduces cerebral edema, preserves tight junction protein expression, abolishes microthrombosis, increases eNOS phosphorylation, prevents cerebral vasospasm, and inhibits neuronal apoptosis. Aim 1 is to determine whether adropin confers protection against acute neural injury after SAH when given in a clinically translatable timepoint after SAH. In Aim 2, we will study mediators that regulate Enho gene expression in the setting of SAH. In Aim 3, we will study whether adropin neurovascular protection is mediated via eNOS activity. We expect this study will provide novel knowledge on adropin-mediated protection against acute neural injury after SAH. The significance of this study is that it is directly translatable and the first to investigate the fundamentals of adropin regulation in brain endothelial cells after SAH. This study will provide the preclinical data for a Phase 1/2 human clinical trial in SAH patients.

抽象的 蛛网膜下腔出血（SAH）相关的脑梗死发生的急性神经损伤发生在30-40％ 在初始出血，导致死亡和残疾的患者，并且与3-最密切相关 一个月的结果。长期认知缺陷也有很大的速度。当前对 萨克后脑梗塞的病理生理学表明涉及一氧化氮的损伤级联（NO） 生物利用度和氧化应激。在正常条件下，没有信号通路调节脑血 通过介导脑血管舒张和抑制血小板粘附来流动。但是，使用SAH，红细胞 裂解并释放血红蛋白，这是一种痉挛性。血红蛋白清除否；刺激生产 一氧化氮合酶（NOS）抑制剂（ADMA）；并产生活性氧（ROS）和氮 物种（RN）。我们认为，最近被识别的肽Horsene Adropin是一个有前途的治疗靶点 萨哈后脑梗塞。我们的小组和其他人表明adropin在大脑中绝对表达， 调节内皮一氧化氮合酶（ENOS）途径，与氧化物应激标记相关， 并响应模拟缺血而降低脑内皮通透性。我们的假设是adropin 赋予侵害急性神经损伤的保护后萨拉后脑梗塞。我们的总体目标 建议是证明adropin在SAH中的受保护作用，并研究了潜在的分子和 该保护的细胞机制。我们的初步数据支持了这一假设 降低脑adropin的表达，并用A SAH模型中的β-肌动蛋白驱动的adropin转化（ADRTG）或合成adropin处理可减少 脑水肿，保留紧密的连接蛋白表达，废除微骨质病，增加了eNOS 目标1是确定磷酸化，防止脑血管痉挛并抑制神经元凋亡。 Adropin在SAH后在SAH后进行急性神经损伤的保护 SAH之后的时间点。在AIM 2中，我们将研究调节增强基因表达的介体 SAH。在AIM 3中，我们将研究是否通过eNOS活性介导adropin神经血管保护。我们 期望这项研究将提供有关adropin介导的针对急性神经损伤的新知识 SAH。这项研究的意义在于它是可以直接翻译的，并且是第一个研究基本面的 SAH后脑内皮细胞中的adropin调节。这项研究将为一个阶段提供临床前数据 SAH患者的1/2人类临床试验。