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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.

摘要