MiR-126/ABCA1 mediates exosome induced neurorestorative effects after stroke in T2DM mice

MiR-126/ABCA1 介导 T2DM 小鼠中风后外泌体诱导的神经恢复作用

• 批准号: 9473824
• 负责人: JIELI CHEN
• 金额: $ 32.92万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9473824
• 关键词: ATP-Binding Cassette Transporters; Adult; Adverse effects; Affect; Animal Model; Apolipoprotein A-I; Apolipoprotein E; Biological; Biological Process; Blood Vessels; Brain; Cells; Cerebrovascular Disorders; Cerebrum; Cholesterol; Clinical; Cognitive; Communication; Computer software; Control Groups; Data; Diabetes Mellitus; Encapsulated; Endothelial Cells; Exhibits; Female; Gene Proteins; Gene Targeting; Generations; Genes; Impairment; Injury; Ischemic Stroke; Knock-out; Lipids; Mediating; Messenger RNA; MicroRNAs; Molecular Analysis; Morbidity - disease rate; Mus; Neuraxis; Neuroglia; Neurologic; Neurological outcome; Non-Insulin-Dependent Diabetes Mellitus; Pathway Analysis; Pathway interactions; Patients; Pattern; Play; Population; Recovery of Function; Regulator Genes; Risk Factors; Role; Serum; Signal Pathway; Stroke; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Translations; Vascular remodeling; activator 1 protein; base; brain endothelial cell; brain tissue; clinically relevant; diabetic; disability; exosome; experience; functional outcomes; high risk; improved; male; nanosized; neurological recovery; neurorestoration; neurovascular; novel therapeutic intervention; novel therapeutics; outcome forecast; post stroke; protein expression; response; stroke patient; stroke treatment; therapeutic evaluation; therapy design; white matter; white matter damage

Diabetes mellitus (DM) leads to a 3-4 fold higher risk of experiencing ischemic stroke. Stroke in type two DM (T2DM) patients and in animal models increases vascular and white matter (WM) damage in the ischemic brain, and stroke in T2DM patients has a distinct clinical pattern and a poor prognosis compared to non-DM stroke. Exosomes (Exo), are active nano size biological lipid containers, which transport regulatory genes and proteins between cells and form a major biological communication conduit, facilitating a plethora of biological responses. The regulatory molecules contained in the exosome include microRNAs (miRs), which regulate gene translation and play primary roles in mediating a vast range of biological functions. MicroRNA-126 (miR- 126) is an angiogenic microRNA and primarily expressed in endothelial cells (EC). Specific conditional knockout of EC miR-126 (miR-126EC-/-) mice have significantly worse functional outcome after stroke as well as decreased brain miR-126 and ATP-binding cassette transporter A1 (ABCA1) expression. Exosomes derived from EC (EC-Exo) have a high level of miR-126. Based on our robust preliminary data, in this pioneering study, we propose that treatment of stroke with EC-Exo will enhance neurorestorative effects after stroke in T2DM mice, possibly, via the miR-126/ABCA1 signaling pathway. This application includes three Aims. Aim-1: To test the therapeutic effects of EC-Exo on cerebral ischemic stroke in adult male and female T2DM mice. Aim-2: To evaluate whether miR-126 mediates EC-Exo treatment induced neurorestorative effects, we will evaluate the therapeutic effects of treatment of stroke in specific conditional knockout of EC miR-126 (MiR-126EC-/-) and in non-miR-126 knockout control (miR-126fl/fl) T2DM mice with EC-Exo derived from miR-126EC-/- brain ECs (miR-126EC-/-EC-Exo) or EC-Exo derived from wild type miR-126fl/fl brain ECs (miR-126fl/fl-EC-Exo) on vascular and axonal/WM remodeling and neurological and cognitive functional outcome. Aim-3: To test whether ABCA1, an indirect target of miR-126, contributes to EC-Exo treatment induced neurorestorative effects after stroke in adult male T2DM mice, mice with specific knockout of brain ABCA1 (ABCA1-B/-B) and WT ABCA1 knockout control (ABCA1fl/fl) mice will be employed. In this application, we are the first to propose that, generation of miR-126 encapsulated in EC-Exo contributes to its robust therapeutic restorative effects and that miR-126/ABCA1 pathway mediates EC-Exo-induced neurovascular and WM remodeling, and thereby improves stroke neurological and cognitive functional recovery in T2DM mice. This proposal is highly clinically relevant and if successful, will significantly impact the treatment of diabetic stroke, and possibly all stroke patients.

糖尿病（DM）导致3-4倍出现缺血性中风的风险。两型DM中风 （T2DM）患者和动物模型在缺血性中增加血管和白质（WM）损害 与非DM相比 中风。外泌体（EXO）是活性纳米尺寸的生物脂质容器，它们具有调节基因和 细胞之间的蛋白质并形成主要的生物通信导管，促进了很多生物学 回答。外泌体中包含的调节分子包括调节的microRNA（miR） 基因翻译和在介导广泛的生物学功能中起主要作用。 microRNA-126（mir- 126）是一种血管生成microRNA，主要在内皮细胞（EC）中表达。具体条件 EC miR-126（miR-126ec - / - ）小鼠的敲除卒中功能结果明显较差 随着脑miR-126和ATP结合盒式转运蛋白A1（ABCA1）表达减少。外泌体 源自EC（EC-EXO）的miR-126水平高。基于我们强大的初步数据 开创性研究，我们建议用EC-EXO治疗中风将在 可能通过miR-126/abca1信号通路中的T2DM小鼠中风。该应用程序包括三个 目标。 AIM-1：测试EC-EXO对成年男性和女性脑缺血性中风的治疗作用 T2DM小鼠。 AIM-2：评估miR-126是否介导了EC-EXO治疗诱导神经读剂 效果，我们将评估中风治疗在EC的特定条件敲除中的治疗作用 miR-126（miR-126ec - / - ）和在非MIR-126敲除控制（miR-126fl/fl）T2DM小鼠中，EC-EXO得出 来自miR-126ec - / - 脑ECS（miR-126ec - / - ec-Exo）或源自野生型miR-126fl/fl脑ECS的EC-EXO （miR-126FL/FL-EC-EXO）在血管和轴突/WM重塑以及神经和认知功能上 结果。 AIM-3：测试miR-126的间接目标ABCA1是否有助于EC-EXO治疗 中风后诱导的神经探究作用在成年雄性T2DM小鼠中，具有特定脑敲除大脑的小鼠 将使用ABCA1（ABCA1-B/-B）和WT ABCA1敲除控制（ABCA1FL/FL）小鼠。在此应用程序中 我们是第一个提出的，封装在EC-EXO中的miR-126的产生有助于其强大 治疗性修复作用，而miR-126/abca1途径介导了EC-EXO诱导的神经血管 和WM重塑，从而改善了T2DM中的中风神经和认知功能恢复 老鼠。该提案在临床上具有很高的相关性，如果成功，将对处理的治疗产生重大影响 糖尿病性中风，可能是所有中风患者。