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.

摘要 Adropin是最近发现的一种在脑中大量表达的高度保守的多肽。阿德罗平 在内皮功能、胰岛素敏感性和代谢的调节中起关键作用。最近的调查结果 从我们的小组和其他人揭示，阿霉素可以显着降低大鼠脑内皮细胞的通透性， 人血管内皮细胞临床研究表明，低血浆水平的 肾上腺素和内皮功能障碍在几种人类疾病。血管内皮功能障碍是 缺血性中风的发病机制。一氧化氮（NO）的产生不足， 内皮型一氧化氮合酶（eNOS）是导致糖尿病内皮功能障碍的关键因素， 肥胖和高脂血症是脑卒中的重要危险因素。我们的假设是肾上腺素 通过减少对血脑屏障（BBB）/神经血管的损伤来防止缺血性卒中损伤 单位我们的总体目标是证明肾上腺素在缺血性卒中中的保护作用， 研究这种保护的潜在分子机制。我们的初步数据支持这一假设 通过显示用合成的阿霉素治疗显著降低了小鼠中风模型中的脑损伤， 这与eNOS磷酸化的显著增加和BBB损伤的减少有关。此外，委员会认为， 在eNOS缺陷小鼠中，Adropin保护作用完全消失，表明eNOS依赖性 Adropin在中风中保护作用的机制。目的1是确定Adropin的作用 治疗对缺血性中风小鼠模型中的梗塞大小和长期功能恢复的影响。在目标2中， 将决定阿霉素降低内皮功能障碍，氧化应激， 和神经炎症对缺血性卒中后BBB功能的影响。在目标3中，我们将测试 与年龄、性别、种属和共病（肥胖和糖尿病）相关的阿霉素疗效。是我们 预期本研究将为肾上腺素在缺血性脑损伤中的保护作用提供重要的知识。 中风预计这些结果将产生重要的积极影响，因为它们将为以下方面奠定基础： 扩大了关于阿霉素在脑缺血中的保护作用的临床前工作，并将确定新的 以及急需的方法来减少中风后神经血管损伤的破坏性后果。