Neurorestorative therapy of stroke with HUCBC in T2DM rats

HUCBC 对 T2DM 大鼠中风的神经恢复治疗

• 批准号: 8522682
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522682
• 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; Diabetic Angiopathies; 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; 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 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

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) 导致缺血性中风的风险增加 3-4 倍。此外，与非糖尿病卒中患者相比，糖尿病卒中患者更容易出现更多且更早的白质（WM）高强度病变。中风后 2-3 小时用组织纤溶酶原激活剂 (rtPA) 治疗中风可减少非糖尿病大鼠的病变体积。然而，tPA 不会减少病变体积，也不会改善功能结果，反而会增加 DM 大鼠缺血脑中脑出血和血脑屏障 (BBB) 渗漏的发生率。此外，用骨髓基质细胞 (BMSC) 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 中风大鼠的功能结果。因此，非糖尿病人群中风的有效治疗可能不一定会转移到糖尿病人群中，这促使需要开发专门设计用于减少糖尿病人群中风后神经功能缺损的治疗方法。人脐带血细胞（HUCBC）的成熟度低于骨髓，即使只有半匹配也可以成功使用。我们发现，在大脑中动脉闭塞（MCAo）后1或3天开始用HUCBC治疗中风可改善DM大鼠神经功能的恢复。因此，基于我们可靠的初步数据，我们建议采用一种新颖的临床相关方法，使用 HUCBC 治疗二型糖尿病 (T2DM) 大鼠的中风。以下具体目标和相关假设将 HUCBC 开发为一种安全且新颖的神经恢复疗法，可改善接受 MCAo 的 T2DM 大鼠的神经功能并减少 WM 功能障碍和血管损伤。目标 1 将研究 HUCBC 治疗 T2DM 大鼠中风的安全性和治疗效果。另外，我们将测试HUCBC联合tPA对T2DM大鼠的治疗效果；我们将确定 tPA 对 HUCBC 的任何潜在不利影响，并确定 HUCBC 治疗是否可以减轻 tPA 对 T2DM 大鼠的不利影响。在目标 2 中，我们将阐明 HUCBC 对 T2DM 大鼠中风后 WM 重塑的神经恢复作用。 HUCBC 作为治疗剂具有巨大的商业化潜力，因为它们易于获得且易于分离，且没有严重的伦理和技术问题。如果需要，HUCBC 可用于自体移植或同种异体移植。 HUCBC 对糖尿病脑中风后神经功能恢复的潜在治疗作用以及 DM 大鼠缺血脑的相应重塑开启了巨大的可能性。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。