Neuroprotective therapy of stroke with HUCNC and simvastatin

描述（由申请人提供）：迫切需要开发专门设计的治疗方法来减少中风后的神经功能障碍。人脐带血细胞（hucbc）治疗剂量依赖性改善脑卒中后功能结局。ucbc与移植物抗宿主病（GVHD）的风险较低相关，并且ucbc比成人骨髓干细胞更年轻，因此可能更有活力。我们的初步数据显示，亚治疗剂量的辛伐他汀与hucbc的联合使用增加了外源性给药细胞向缺血性脑的迁移，并增加了卒中后基于细胞的治疗结果。因此，用药物改变缺血组织以促进细胞接受微环境可能会扩大细胞治疗的治疗方式。我们建议，通过在缺血脑组织内创造一个微环境，促进细胞诱导大脑可塑性，使组织更容易接受给药细胞，从而增强细胞基础治疗。在本提案中，我们试图研究辛伐他汀和HUCBC联合治疗的效果，以扩大HUCBC细胞治疗的治疗效果，改善脑卒中后的功能结局。我们将在大鼠栓塞性中风的临床相关模型中测试细胞和药物联合治疗的效果。在Aim 1中，我们假设hubc和辛伐他汀联合治疗卒中可促进成年大鼠神经功能结局的加性或超加性改善。在Aim 2中，我们研究了HUCBC和辛伐他汀联合治疗是否会增加HUCBC向缺血性脑的迁移。我们假设，HUCBC和辛伐他汀联合治疗增加了基质衍生因子1 （SDF1）的表达，并增强了HUCBC在缺血性脑中的归家/迁移和存活。缺血性脑中HUCBC数量的增加增加了脑卒中后的功能预后。hucbc和辛伐他汀联合治疗可减少大鼠缺血性脑梗死体积，促进血管生成和神经发生。我们将阐明hucbc和辛伐他汀联合治疗的效果，目的是开发一种可行的恢复性治疗，转化为卒中人群。我们的研究是一个原型和一个原理的证明，旨在增强对外源性细胞治疗中风的治疗反应。

DESCRIPTION (provided by applicant): There is a compelling need to develop therapeutic approaches specifically designed to reduce neurological deficits after stroke. Human umbilical cord blood cells (HUCBCs) treatment dose-dependently improves functional outcome after stroke. UCBCs are associated with a lower risk of graft-versus-host disease (GVHD), and UCBCs are younger than adult bone marrow stem cells and therefore potentially more vigorous. Our preliminary data show that the combination of sub-therapeutic doses of simvastatin with HUCBCs increases exogenously administered cell migration into the ischemic brain, and additively improves the cell-based therapeutic outcome after stroke. Thus, altering the ischemic tissue with agents to promote a cell receptive microenvironment may amplify the therapeutic modality of cell-based therapy. We propose that cell-based therapy can be enhanced by making the tissue more receptive to the administered cells by creating a microenvironment within the ischemic cerebral tissue that facilitates cell-based induction of brain plasticity. In this proposal, we seek to investigate the effect of combination of simvastatin and HUCBCs to amplify the therapeutic effect of HUCBC cell-based therapy, to improve the functional outcome after stroke. We will test the effects of combination cell-based and pharmacological therapies in a clinically relevant model of embolic stroke in rat. In Aim 1, we hypothesize that the combination treatment of stroke with HUCBCs and simvastatin promotes additive or super-additive improvement of neurological functional outcome in adult rats. In Aim 2, we investigate whether combination treatment with HUCBCs and simvastatin increases HUCBC migration into the ischemic brain. We hypothesize, that combination treatment with HUCBCs and simvastatin increases stromal derived factor 1 (SDF1) expression and enhances HUCBC homing/migration and survival in the ischemic brain. The increased HUCBC number in the ischemic brain increases functional outcome after stroke. Combination treatment with HUCBCs and simvastatin reduces infarct volume, and enhances angiogenesis and neurogenesis in the ischemic brain in rats. We will elucidate the effect of combination HUCBCs and simvastatin therapy with the intention of developing a viable restorative therapy to translate to the stroke population. Our study is a prototype and a proof of principle designed to augment the therapeutic response to the administration of exogenous cells for the treatment of stroke. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of morbidity and long-term disability. Treatment of stroke has taken essentially two approaches, cellular and pharmacological therapy. We propose to combine cell and pharmacological treatment, to enhance recovery of neurological function post stroke. Our preliminary data show that the human umbilical cord blood cells (HUCBCs) treatment of stroke improves functional outcome. Combination of sub- therapeutic doses of simvastatin with HUCBCs increases exogenously administered cell migration into the ischemic brain and additively improves the therapeutic outcome after stroke. Thus, we propose that HUCBC cell-based therapy can be enhanced by making the tissue more receptive to the administered cells by creating a microenvironment within the ischemic cerebral tissue that facilitates cell-based induction of brain plasticity. A clinically relevant embolic middle cerebral artery occlusion (MCAo) rat model will be used in this study, which will provide new and important data regarding novel therapeutic targets for stroke recovery.