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

• 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
• 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

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3-4倍出现缺血性中风的风险。高血糖和糖尿病引起了导致血管内皮细胞功能障碍，血管通透性增加和缺血性中风后恢复不良的级联事件。中风后，糖尿病动物表现出严重受伤的白质（WM）。 DM和非DM受试者之间的中风治疗也有不同的反应。在非DM人群中，有效的中风治疗可能不一定会转移到DM人群中，这促使需要开发专门设计的治疗方法，以减少DM人群中风后的神经缺陷。我们的初步数据表明，T2DM显着降低了循环中和小鼠缺血性脑中MicroRNA-126（miR-126）和Angiopoietin-1（Ang1）的表达。从中风后3天开始，在T2DM小鼠中，人脐带血细胞（HUCBC）治疗中风的治疗可显着提高神经功能的恢复，并增加缺血性脑中的miR-126和ANG1表达。因此，基于我们强大的初步数据，我们建议使用HUCBC来治疗T2DM小鼠中的中风，并研究通过MiR-126通过miR-126封装在外泌体/微泡中（EMV）在介导Hucbcs hucbcs中介导Hucbcs中的细胞体/微囊泡（EMV）的作用。该应用程序包括三个目标。 AIM 1将测试miR-126是否介导HUCBC治疗在T2DM小鼠的中风后诱导的神经疏松作用。我们假设miR-126介导了HUCBC治疗诱导的血管完整性，轴突生长和WM重塑，并改善了T2DM小鼠中风后的功能结果。 AIM 2将测试HUCBC产生的miR-126是否通过EMV转移到脑内皮细胞（BEC）和实质细胞中。我们假设HUCBCS分泌包含由BEC和实质细胞吸收的miR-126的EMV。 AIM 3将研究miR-126 ANG1的调节是否促进了T2DM小鼠中风后HUCBC诱导的神经养生作用。我们假设：1）T2DM小鼠中卒中的HUCBC治疗会增加缺血性脑中的Ang-1信号传导活性； 2）miR-126调节ANG1的表达，从而调节血管重塑，轴突产物和少突胶质细胞的生存和分化； 3）用ANG1模拟肽恢复ANG1将挽救T2DM小鼠中风后MiR-126敲低的MiR-126敲低作用。在此应用中，我们第一个提出，HUCBC在EMV中封装的miR-126的产生有助于其可靠的治疗性修复效果，并且miR-126及其对ANG-1的调节介导了HUCBC诱导的神经血管造成的神经血管和WM重塑，从而改善了T2DM小鼠的Stroke功能恢复。该提案在临床上高度相关，如果成功，将显着影响糖尿病的治疗以及所有中风患者