Neurovascular Protection by Adropin in Ischemic Stroke

Adropin 在缺血性中风中的神经血管保护作用

基本信息

批准号：
10161626
负责人：
Eduardo Jesus Candelario-Jalil
金额：
$ 34.52万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161626
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 therapeutic intervention overexpression polypeptide post stroke pre-clinical protective effect protective efficacy sex stroke model stroke outcome stroke patient

项目摘要

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 Adropin 是最近发现的一种高度保守的多肽，在大脑中大量表达。阿德罗平在内皮功能、胰岛素敏感性和代谢的调节中起着关键作用。最近的发现我们小组和其他人的研究表明，adropin 可以显着降低大鼠大脑中的内皮细胞通透性，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 adropin 和几种人类疾病中的内皮功能障碍。内皮功能障碍是关键因素之一影响缺血性中风发病机制的因素。一氧化氮 (NO) 生成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、高脂血症是中风的重要危险因素。我们的假设是 adropin 赋予通过减少对血脑屏障 (BBB)/神经血管的损害来预防缺血性中风损伤单元。我们在本提案中的总体目标是证明阿德洛平在缺血性中风和中风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证明合成阿德洛品治疗可显着减少小鼠中风模型中的脑损伤，这与 eNOS 磷酸化的显着增加和血脑屏障损伤的减少有关。而且， eNOS 缺陷小鼠中 adropin 的保护作用完全消失，表明 eNOS 依赖性 adropin 对中风的保护作用的机制。目标 1 是确定 adropin 的作用对缺血性中风小鼠模型的梗死面积和长期功能恢复的治疗。在目标 2 中，我们将确定 adropin 减少内皮功能障碍、氧化应激、缺血性中风后神经炎症对血脑屏障功能的影响。在目标 3 中，我们将测试神经保护作用 adropin 的功效与年龄、性别、物种和合并症（肥胖和糖尿病）有关。这是我们的期望这项研究将为阿德洛平在缺血性脑损伤中的保护功效提供重要的知识。中风。这些结果预计将产生重要的积极影响，因为它们将为扩大了阿德洛平对脑缺血保护作用的临床前研究，并将确定新的以及减少中风后神经血管损伤的破坏性后果的急需方法。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Receptor-interacting protein kinase 2 (RIPK2) profoundly contributes to post-stroke neuroinflammation and behavioral deficits with microglia as unique perpetrators.

受体相互作用蛋白激酶 2 (RIPK2) 极大地促进了中风后神经炎症和行为缺陷，而小胶质细胞是唯一的肇因。

DOI：
发表时间：
2023-09-30
期刊：
影响因子：
0
作者：
Larochelle, Jonathan;Tishko, Ryland J;Yang, Changjun;Ge, Yong;Phan, Leah T;Gunraj, Rachel E;Stansbury, Sofia M;Liu, Lei;Mohamadzadeh, Mansour;Khoshbouei, Habibeh;Candelario
通讯作者：
Candelario

Protective roles of adropin in neurological disease.

阿德洛品在神经系统疾病中的保护作用。