Neuroprotective therapy of stroke with HUCNC and simvastatin

HUCNC 和辛伐他汀对中风的神经保护治疗

• 批准号: 7801467
• 负责人: JIELI CHEN
• 金额: $ 17.69万
• 依托单位: SANERON CCEL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7801467
• 关键词: Adjuvant; Adult; Blood Cell Count; Blood Cells; Bone Marrow Stem Cell; Brain; Cell Therapy; Cells; Cerebrum; Combined Modality Therapy; Data; Dose; Figs - dietary; Human; Infarction; Intention; Middle Cerebral Artery Occlusion; Modality; Modeling; Mono-S; Morbidity - disease rate; Nervous System Physiology; Neurologic; Outcome; Pharmacological Treatment; Population; Rattus; Recovery; Regulation; Risk; Simvastatin; Stroke; Testing; Therapeutic; Therapeutic Effect; Tissues; Translating; Treatment Efficacy; Umbilical Cord Blood; angiogenesis; base; brain tissue; cell motility; clinically relevant; design; disability; functional outcomes; graft vs host disease; improved; migration; neurogenesis; new therapeutic target; post stroke; prototype; public health relevance; response; stroke recovery; stroke therapy; young adult

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.

描述（由申请人提供）：迫切需要开发专门为减少中风后神经缺陷而设计的治疗方法。人脐带血细胞（HUCBCS）治疗剂量依赖性地改善了中风后的功能结果。 UCBC与较低的移植物抗宿主疾病（GVHD）有关，UCBC比成年骨髓干细胞年轻，因此可能更剧烈。我们的初步数据表明，辛伐他汀亚治疗剂量与HUCBCS的结合增加了外源给予细胞迁移到缺血性大脑中，并添加地改善了中风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放大基于细胞的治疗的治疗方式。我们建议，可以通过在缺血性脑组织中建立微环境，从而使组织更接受组织，从而增强基于细胞的疗法，从而促进基于细胞的脑可塑性的诱导。在该提案中，我们试图研究辛伐他汀和HUCBC的组合以扩大基于HUCBC细胞的治疗的治疗作用，以改善中风后的功能结果。我们将测试基于组合细胞和药理学疗法的临床相关模型的栓塞中风模型的影响。在AIM 1中，我们假设中风与HUCBC和辛伐他汀的联合治疗可促进成年大鼠神经功能结果的添加剂或超添加性改善。在AIM 2中，我们研究了与HUCBCS和辛伐他汀的组合治疗是否会增加HucBC迁移到缺血性大脑中。我们假设，与HUCBC和辛伐他汀的结合处理增加了基质衍生因子1（SDF1）的表达，并增强了缺血性大脑中Hucbc Housing/迁移和存活率。缺血性大脑中的HUCBC数量增加会增加中风后的功能结果。与HUCBC和辛伐他汀的联合治疗可减少梗死体积，并增强大鼠缺血性脑中的血管生成和神经发生。我们将阐明HUCBC和辛伐他汀疗法的作用，目的是开发可行的恢复性疗法以转化为中风人群。我们的研究是一个原型和原理证明，旨在增加对外源细胞治疗中风的治疗反应的治疗反应。 公共卫生相关性： 中风是发病率和长期残疾的第三主要原因。中风的治疗基本上采用了两种方法，分别是细胞和药理疗法。我们建议将细胞和药理治疗结合起来，以增强中风后神经功能的恢复。我们的初步数据表明，人类脐带血细胞（HUCBC）的中风治疗可改善功能结果。辛伐他汀与HUCBC的亚治疗剂量的结合增加了外源给予细胞迁移到缺血性大脑中，并加上卒中后的治疗结果。因此，我们提出，通过在缺血性脑组织中建立微环境，可以使组织更容易接受，从而增强基于HUCBC细胞的疗法，从而促进基于细胞的脑可塑性的诱导。本研究将使用与临床相关的栓塞中大脑动脉闭塞（MCAO）大鼠模型，该模型将提供有关中风恢复的新型治疗靶标的新的重要数据。