Neurorestorative therapy of stroke with HUCBC in T2DM rats

描述（由申请人提供）：糖尿病（DM）导致发生缺血性卒中的风险增加3-4倍。此外，DM卒中患者比非DM卒中患者更容易出现更多和更早的白色高强度病变。在中风后2-3小时用组织纤溶酶原激活剂（rtPA）治疗中风可减少非DM大鼠的病变体积。然而，tPA不能减少病变体积，也不能改善功能结果，但会增加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）治疗中风改善了野生型（WT）中风大鼠的功能结局，但在DM中风大鼠中没有。因此，在非DM人群中有效的卒中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用于减少DM人群卒中后神经功能缺损的治疗方法。人脐带血细胞（HUCBCs）比骨髓成熟度低，即使只有一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HUCBCs治疗中风可改善DM大鼠神经功能的恢复。因此，在一种新的临床相关方法中，基于我们稳健的初步数据，我们建议使用HUCBCs治疗2型DM（T2 DM）大鼠的卒中。以下具体目标和相关假设将开发HUCBC作为一种安全和新型的神经恢复疗法，可改善患有MCAo的T2 DM大鼠的神经功能并减少WM功能障碍和血管损伤。目的1研究人脐带血细胞治疗2型糖尿病大鼠脑卒中的安全性和疗效。此外，我们将测试HUCBC与tPA组合在T2 DM大鼠中的治疗效果;我们将鉴定tPA对HUCBC的任何潜在不良作用，并确定HUCBC治疗是否减弱tPA在T2 DM大鼠中诱导的不良作用。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作为治疗剂具有巨大的商业化潜力，因为它们容易获得并且易于分离而没有严重的伦理和技术问题。如果需要，HUCBCs可用于自体移植或同种异体移植。HUCBC对糖尿病脑卒中后神经功能恢复的潜在治疗影响以及DM大鼠缺血性脑的相应重塑开辟了巨大的可能性。该建议具有高度临床相关性，如果成功，将显著影响糖尿病患者和可能所有卒中患者的治疗。

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.