Neurorestorative therapy of stroke with HUCBC in type two diabetic mice

HUCBC 对二型糖尿病小鼠中风的神经恢复治疗

基本信息

批准号：
8811487
负责人：
JIELI CHEN
金额：
$ 32.48万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8811487
关键词：
Angiopoietin-1 Animals Biological Blood Cells Blood Circulation Blood Vessels Brain CD34 gene Cause of Death Cell Therapy Cell physiology Cells Cerebrum Complex Data Diabetes Mellitus Diabetic mouse Encapsulated Endothelial Cells Event Exhibits Functional disorder Generations Genes Guidelines Health Human Hyperglycemia Industry Injury Ischemic Stroke Lesion Mediating Medical MicroRNAs Microvascular Dysfunction Morbidity - disease rate Mus Nervous System Physiology Neurologic Neurons Non-Insulin-Dependent Diabetes Mellitus Oligodendroglia Pathogenesis Pathway interactions Patients Peptides Peripheral Blood Mononuclear Cell Plasma Population RNA Sequences Rattus Recovery Recovery of Function Regulation Role Serum Signal Transduction Stroke Testing Therapeutic Therapeutic Effect Time Umbilical Cord Blood Untranslated RNA Vascular Diseases Vascular Endothelial Cell Vascular Permeabilities Vascular remodeling Vesicle angiogenesis base brain tissue clinically relevant cost design diabetic diabetic patient disability effective therapy experience functional outcomes high risk improved injured intercellular communication loss of function macrovascular disease mimetics neovascularization neurorestoration non-diabetic novel response restoration social stroke therapy transcriptome sequencing white matter

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus (DM) leads to a 3-4 fold higher risk of experiencing ischemic stroke. Hyperglycemia and diabetes instigate a cascade of events leading to vascular endothelial cell dysfunction, increased vascular permeability and poor recovery after ischemic stroke. Diabetic animal's exhibit more severely injured white matter (WM) than non-DM animals after stroke. There is also a differential response to treatment of stroke between DM and non-DM subjects. Effective therapy of stroke in the non-DM population may not necessarily transfer to the DM population, prompting the need to develop therapeutic approaches specifically designed to reduce neurological deficits after stroke in the DM population. Our preliminary data show that T2DM significantly decreases microRNA-126 (miR-126) and Angiopoietin-1 (Ang1) expression in the circulation and in the ischemic brain of mice. Human umbilical cord blood cell (HUCBC) treatment of stroke in T2DM mice starting at 3 days after stroke significantly improves recovery of neurological function as well as increases miR-126 and Ang1 expression in the ischemic brain. Therefore, based on our robust preliminary data, we propose to use HUCBCs for the treatment of stroke in the T2DM mice and to investigate the role of intercellular communication via miR-126 encapsulated within Exosomes/Microvesicles (EMVs) in mediating the therapeutic benefit on HUCBCs for ischemic stroke. This application includes three Aims. Aim 1 will test if miR-126 mediates HUCBC treatment induced neurorestorative effects after stroke in T2DM mice. We hypothesize that miR-126 mediates HUCBC treatment-induced vascular integrity, axonal outgrowth, and WM remodeling, and improves functional outcome after stroke in T2DM mice. Aim 2 will test whether miR-126 generated by HUCBCs is transferred to brain endothelial cells (BECs) and parenchymal cells via EMVs. We hypothesize that HUCBCs secrete EMVs containing miR-126 which are taken up by BECs and parenchymal cells. Aim 3 will investigate whether miR-126 regulation of Ang1 promotes the HUCBC-induced neurorestorative effects after stroke in T2DM mice. We hypothesize that: 1) HUCBC treatment of stroke in T2DM mice increases Ang-1 signaling activity in the ischemic brain; 2) miR-126 regulates Ang1 expression and thereby regulates vascular remodeling, axonal outgrowth and oligodendrocyte survival and differentiation; 3) Restoration of Ang1 with an Ang1 mimetic peptide will rescue the neurorestorative effects of knockdown of miR-126 in HUCBC after stroke in T2DM mice. In this application, we are the first to propose that, generation of miR-126 encapsulated in EMVs by HUCBCs contributes to its robust therapeutic restorative effects and that miR-126 and its regulation of Ang-1 mediate HUCBC-induced neurovascular and WM remodeling, and thereby improve stroke functional recovery in T2DM mice. This proposal is highly clinically relevant and if successful, will significantly impact the treatment of diabetic and possibly all stroke patients

描述（由申请人提供）：糖尿病 (DM) 导致缺血性中风的风险增加 3-4 倍。高血糖和糖尿病会引发一系列事件，导致血管内皮细胞功能障碍、血管通透性增加以及缺血性中风后恢复不良。中风后，糖尿病动物的白质 (WM) 损伤比非糖尿病动物更严重。糖尿病和非糖尿病受试者对中风治疗的反应也存在差异。非糖尿病人群中风的有效治疗不一定会转移到糖尿病人群中，因此需要开发专门用于减少糖尿病人群中风后神经功能缺损的治疗方法。我们的初步数据表明，T2DM 显着降低小鼠循环系统和缺血脑中的 microRNA-126 (miR-126) 和血管生成素-1 (Ang1) 表达。从中风后 3 天开始，对 T2DM 小鼠中风进行人脐带血细胞 (HUCBC) 治疗，可显着改善神经功能的恢复，并增加缺血脑中 miR-126 和 Ang1 的表达。因此，基于我们可靠的初步数据，我们建议使用 HUCBC 治疗 T2DM 小鼠中风，并研究通过封装在外泌体/微泡 (EMV) 内的 miR-126 进行的细胞间通讯在介导 HUCBC 治疗益处中的作用用于缺血性中风。该应用程序包括三个目标。目标 1 将测试 miR-126 是否介导 HUCBC 治疗在 T2DM 小鼠中风后诱导的神经恢复作用。我们假设 miR-126 介导 HUCBC 治疗诱导的血管完整性、轴突生长和 WM 重塑，并改善 T2DM 小鼠中风后的功能结果。目标 2 将测试 HUCBC 产生的 miR-126 是否通过 EMV 转移至脑内皮细胞 (BEC) 和实质细胞。我们假设 HUCBC 分泌含有 miR-126 的 EMV，并被 BEC 和实质细胞吸收。目标 3 将研究 miR-126 对 Ang1 的调节是否促进 HUCBC 诱导的 T2DM 小鼠中风后神经恢复作用。我们假设：1) HUCBC 治疗 T2DM 小鼠中风可增加缺血大脑中的 Ang-1 信号活性； 2) miR-126 调节 Ang1 表达，从而调节血管重塑、轴突生长和少突胶质细胞存活和分化； 3) 用 Ang1 模拟肽恢复 Ang1 将挽救 T2DM 小鼠中风后 HUCBC 中 miR-126 敲低的神经恢复作用。在本申请中，我们首次提出，HUCBC 封装在 EMV 中的 miR-126 的产生有助于其强大的治疗恢复作用，并且 miR-126 及其对 Ang-1 的调节介导 HUCBC 诱导的神经血管和 WM 重塑，从而改善 T2DM 小鼠的中风功能恢复。该提议具有高度的临床相关性，如果成功，将显着影响糖尿病患者以及可能所有中风患者的治疗