Neurovascular Protection by Adropin in Ischemic Stroke

Adropin 在缺血性中风中的神经血管保护作用

• 批准号: 9920225
• 负责人: Eduardo Jesus Candelario-Jalil
• 金额: $ 35.15万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920225
• 关键词: Adult; Age; Alteplase; Anatomy; Animal Model; Attenuated; Basic Science; Biological Availability; Blood - brain barrier anatomy; Blood Vessels; Blood flow; Brain; Brain Injuries; Brain Ischemia; Cells; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Clinical Research; Data; Development; Diabetes Mellitus; Endothelium; Enzyme-Linked Immunosorbent Assay; Exposure to; Extravasation; Flow Cytometry; Foundations; Functional disorder; Gelatinase B; Generations; Genes; Goals; Homeostasis; Hospitals; Human; Hyperlipidemia; Immunoblotting; Incidence; Infarction; Injury; Ischemia; Ischemic Stroke; Knockout Mice; Knowledge; Magnetic Resonance Imaging; Measurement; Mediating; Mediator of activation protein; Metabolism; Mission; Modeling; Molecular; Mus; Myocardial Ischemia; NADPH Oxidase; NOS3 gene; National Institute of Neurological Disorders and Stroke; Neurological outcome; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Pathogenesis; Peptides; Permeability; Peroxonitrite; Pharmaceutical Preparations; Phosphorylation; Plasma; Plasma Proteins; Play; Production; Public Health; Rattus; Reaction; Recovery of Function; Regulation; Reporter; Research; Risk Factors; Role; Stroke; Superoxides; Techniques; Testing; Therapeutic; Therapeutic Uses; Time; Transgenic Mice; Tumor-infiltrating immune cells; Vascular Endothelial Cell; Wild Type Mouse; Work; aged; angiogenesis; base; behavioral outcome; blood damage; blood-brain barrier function; blood-brain barrier permeabilization; brain endothelial cell; clinically relevant; cognitive testing; comorbidity; disability; endothelial dysfunction; expectation; experimental study; genetic approach; human disease; improved; innovation; insulin sensitivity; mortality; mouse model; nervous system disorder; neurogenesis; neuroinflammation; neurological recovery; neuron loss; neuroprotection; neurotoxicity; neurovascular; neurovascular injury; neurovascular unit; novel; novel strategies; novel therapeutics; overexpression; polypeptide; post stroke; pre-clinical; protective effect; protective efficacy; sex; stroke model; stroke outcome; stroke patient

ABSTRACT Adropin is a recently identified and highly conserved polypeptide abundantly expressed in the brain. Adropin plays a critical role in the regulation of endothelial function, insulin sensitivity, and metabolism. Recent findings from our group and others reveal that adropin can significantly reduce endothelial permeability in rat brain and human vascular endothelial cells. Clinical studies show a significant association between low plasma levels of adropin and endothelial dysfunction in several human diseases. Endothelial dysfunction is one of the critical factors contributing to the pathogenesis of ischemic stroke. Deficient production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) is a key factor contributing to endothelial dysfunction in diabetes, obesity, and hyperlipidemia, which are important risks factors for stroke. Our hypothesis is that adropin confers protection against ischemic stroke injury by reducing damage to the blood-brain barrier (BBB)/neurovascular unit. Our overall goal in this proposal is to demonstrate the protective role of adropin in ischemic stroke and investigate the underlying molecular mechanisms of this protection. Our preliminary data support this hypothesis by showing that treatment with synthetic adropin dramatically reduces brain injury in a mouse stroke model, which was associated with a significant increase in eNOS phosphorylation and reduced BBB damage. Moreover, adropin protection was completely abolished in eNOS deficient mice suggesting an eNOS-dependent mechanism underlying the protective effects of adropin in stroke. Aim 1 is to determine the effects of adropin treatment on infarct size and long-term functional recovery in a mouse model of ischemic stroke. In Aim 2, we will determine the ability of adropin to reduce the detrimental effects of endothelial dysfunction, oxidative stress, and neuroinflammation on BBB function following ischemic stroke. In Aim 3, we will test the neuroprotective efficacy of adropin in relation to age, sex, species, and comorbid conditions (obesity and diabetes). It is our expectation that this study will provide significant knowledge on the protective efficacy of adropin in ischemic stroke. Such results would be expected to have an important positive impact, since they would set the stage for expanded preclinical work on the protective efficacy of adropin in cerebral ischemia, and would identify novel and much-needed approaches to reduce the devastating consequences of neurovascular injury after stroke.

抽象的 赤霉素是一种最近在大脑中表达的最近鉴定出的高度保守的多肽。 adropin 在调节内皮功能，胰岛素敏感性和代谢中起关键作用。最新发现 来自我们的小组和其他人，表明adropin可以显着降低大鼠大脑中的内皮渗透性 人血管内皮细胞。临床研究表明，低血浆水平之间存在显着关联 多种人类疾病中的adropin和内皮功能障碍。内皮功能障碍是关键之一 导致缺血性中风的发病机理的因素。一氧化氮（NO）的产生不足 内皮一氧化氮合酶（ENOS）是导致糖尿病内皮功能障碍的关键因素， 肥胖和高脂血症，这是中风的重要风险因素。我们的假设是adropin赋予 通过减少对血脑屏障（BBB）/神经血管的损害来防止缺血性中风损伤 单元。我们在该提案中的总体目标是证明艾洛未蛋白在缺血性中风和 研究该保护的潜在分子机制。我们的初步数据支持这一假设 通过显示合成脂蛋白的治疗可大大减少小鼠卒中模型中的脑损伤， 这与eNOS磷酸化和BBB损伤降低有关。而且， 在缺乏eNOS依赖性的eNOS中，adropin的保护完全被废除 adropin在中风中的保护作用的基础机制。目标1是确定adropin的影响 在缺血性中风的小鼠模型中，对梗塞大小和长期功能恢复进行治疗。在AIM 2中，我们 将确定adropin减少内皮功能障碍，氧化应激，氧化应激的有害作用的能力 缺血性中风后BBB功能的神经炎症。在AIM 3中，我们将测试神经保护 与年龄，性别，物种和合并症（肥胖和糖尿病）有关的adropin的功效。这是我们的 期望这项研究将提供有关adropin在缺血性的保护作用的重要知识 中风。期望这样的结果会产生重要的积极影响，因为它们将为 扩展了有关丙氨酸在脑缺血中保护性疗效的临床前工作，并将确定新颖 以及急需的方法，以减少中风后神经血管损伤的毁灭性后果。