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Neurorestorative therapy of stroke with HUCBC in T2DM rats

HUCBC 对 T2DM 大鼠中风的神经恢复治疗

基本信息

批准号：
8627662
负责人：
JIELI CHEN
金额：
$ 21.15万
依托单位：
SANERON CCEL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627662
关键词：
Adult Adverse effects Alteplase Arteriosclerosis Attenuated Autologous Transplantation Axon Blood - brain barrier anatomy Blood Cells Blood Vessels Bone Marrow Brain Brain hemorrhage Caliber Cause of Death Cell Therapy Cell Transplants Cells Child Data Diabetes Mellitus Dose Electron Microscopy Ethics Event Exhibits Extravasation Functional disorder Graft Rejection HLA Antigens Health Homologous Transplantation Hour Human Hyperglycemia Incidence Ischemic Stroke Lesion Mature Bone Medical Microvascular Dysfunction Middle Cerebral Artery Occlusion Mononuclear Myelin Nervous System Physiology Neurologic Neuronal Dysfunction Non-Insulin-Dependent Diabetes Mellitus Patients Peripheral Blood Stem Cell Population Rattus Recovery Relative (related person)Risk Safety Serum Stem cell transplant Stroke Stromal Cells Testing Therapeutic Therapeutic Agents Therapeutic Effect Thick Time Transplant Recipients Transplantation Umbilical Cord Blood Vascular Diseases Vascular Endothelial Cell Vascular Permeabilities angiogenesis base blastomere structure clinically relevant commercialization cost design diabetic diabetic patient disability effective therapy experience functional outcomes glycemic control graft vs host disease high risk improved intravenous administration macrovascular disease myelination neurofilament neuroprotection neurorestoration novel public health relevance social stroke therapy white matter white matter damage

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus (DM) leads to a 3-4 fold higher risk of experiencing ischemic stroke. In addition, DM stroke patients are more prone to develop more and earlier white matter (WM) high-intensity lesions than non DM stroke patients. Treatment of stroke with tissue plasminogen activator (rtPA) at 2-3 hours after stroke decreases lesion volume in non-DM rats. However, tPA does not reduce lesion volume nor improve functional outcome, but increases the incidence of brain hemorrhage and blood-brain barrier (BBB) leakage in the ischemic brain of DM rats. In addition, treatment of stroke with bone marrow stromal cells (BMSCs) improves functional outcome in wild-type (WT)-stroke rats but not in DM-stroke rats. Therefore, 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. Human umbilical cord blood cells (HUCBCs) are less mature than bone marrow and can be successfully used even when there is only a half-match. We found that treatment of stroke with HUCBCs starting at 1 or 3 days after middle cerebral artery occlusion (MCAo) improves recovery of neurological function in DM rats. In a novel and clinically relevant approach, based on our robust preliminary data, we therefore, propose to use HUCBCs for the treatment of stroke in the type two DM (T2DM) rats. The following specific aims and associated hypotheses will develop HUCBC as a safe and novel neurorestorative therapy which improves neurological function and reduces WM dysfunction and vascular damage in T2DM rats subjected to MCAo. In Aim 1 will investigate the safety and therapeutic effect of treatment of stroke in T2DM rats with HUCBCs. In addition, we will test the therapeutic effect of combination of HUCBC with tPA in T2DM rats; we will identify any potential adverse effects of tPA on HUCBCs and determine whether HUCBC treatment attenuates tPA induced adverse effects in T2DM rats. In Aim 2, we will elucidate the neurorestorative effect of HUCBC on WM remodeling after stroke in T2DM rats. HUCBCs have great commercialization potential as therapeutic agents, since they are readily available and easy to isolate without serious ethical and technical problems. HUCBCs can be used for autologous transplantation or allogeneic transplantation, when and if needed. The potential therapeutic impact of HUCBC on recovery on neurological function after stroke in the diabetic brain and the corresponding remodeling of the ischemic brain in DM rats opens enormous possibilities. 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)导致经历缺血性中风的风险增加3-4倍。此外，DM卒中患者比非DM卒中患者更容易出现更多更早的白质(WM)高信号病变。卒中后2-3小时应用组织型纤溶酶原激活剂(RtPA)治疗可减少非糖尿病大鼠的病变体积。然而，tPA并没有减少病变体积，也没有改善功能预后，而是增加了DM大鼠脑缺血后脑出血和血脑屏障(BBB)渗漏的发生率。此外，使用骨髓基质细胞(BMSCs)治疗中风可以改善野生型(WT)中风大鼠的功能结果，但不能改善DM中风大鼠的功能结局。因此，在非糖尿病人群中对中风的有效治疗不一定会转移到糖尿病人群中，这促使需要开发专门设计的治疗方法，以减少糖尿病人群中中风后的神经功能障碍。人脐血细胞(HUCBCs)不如骨髓成熟，即使只有一半匹配的情况下也可以成功使用。我们发现，在大脑中动脉闭塞(MCAO)后1天或3天开始应用HUCBCs治疗卒中，可促进DM大鼠神经功能的恢复。因此，在一种新的和临床相关的方法中，基于我们强大的初步数据，我们建议使用HUCBCs治疗2型糖尿病(T2 DM)大鼠的中风。以下特定目标和相关假设将使HUCBC成为一种安全和新颖的神经修复疗法，改善T2 DM大鼠大脑中动脉阻塞后的神经功能，减少WM功能障碍和血管损害。目的1研究HUCBCs治疗T2 DM大鼠卒中的安全性和疗效。此外，我们还将检测HUCBC和tPA对T2 DM大鼠的治疗效果；我们将确定tPA对HUCBCs的任何潜在不良反应，并确定HUCBC治疗是否减轻tPA对T2 DM大鼠的不良反应。在目的2中，我们将阐明HUCBC对T2 DM大鼠卒中后WM重构的神经修复作用。HUCBCs作为治疗药物具有很大的商业化潜力，因为它们容易获得和容易分离，而不会出现严重的伦理和技术问题。如果需要，人脐血干细胞可用于自体移植或异体移植。HUCBC对糖尿病大鼠卒中后神经功能恢复的潜在治疗作用，以及相应的DM大鼠脑缺血后的脑重构，为糖尿病大鼠提供了巨大的可能性。这项建议具有高度的临床相关性，如果成功，将对糖尿病患者的治疗产生重大影响，可能还会对所有中风患者的治疗产生重大影响。