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）：迫切需要开发专门用于减少卒中后神经功能缺损的治疗方法。人脐带血细胞（HUCBCs）治疗剂量依赖性地改善卒中后的功能结局。UCBCs与移植物抗宿主病（GVHD）的风险较低相关，并且UCBCs比成人骨髓干细胞更年轻，因此可能更有活力。我们的初步数据表明，亚治疗剂量的辛伐他汀与HUCBCs的组合增加了外源性给药的细胞迁移到缺血性脑中，并额外改善了中风后基于细胞的治疗结果。因此，用促进细胞接受微环境的试剂改变缺血组织可以放大基于细胞的治疗的治疗方式。我们提出，可以通过在缺血性脑组织内创造一个微环境，促进基于细胞的脑可塑性诱导，使组织更容易接受给药细胞，从而增强基于细胞的治疗。在这个建议中，我们试图研究辛伐他汀和HUCBCs的组合的效果，以放大基于HUCBCs细胞的治疗效果，以改善卒中后的功能结局。我们将在大鼠栓塞性中风的临床相关模型中测试基于细胞的组合疗法和药理学疗法的效果。在目的1中，我们假设HUCBCs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累加或超累加改善。在目标2中，我们研究HUCBC和辛伐他汀联合治疗是否增加HUCBC向缺血脑的迁移。我们假设，HUCBC和辛伐他汀联合治疗增加了基质衍生因子1（SDF 1）的表达，并增强了HUCBC在缺血脑中的归巢/迁移和存活。缺血性脑中HUCBC数量的增加了卒中后的功能结局。HUCBCs和辛伐他汀联合治疗可减少大鼠缺血性脑梗死体积，并增强血管生成和神经发生。我们将阐明联合HUCBCs和辛伐他汀治疗的效果，目的是开发一种可行的恢复性治疗方法，以转化为中风人群。我们的研究是一个原型和原则的证明，旨在增强对外源性细胞治疗中风的治疗反应。 公共卫生相关性： 中风是发病和长期残疾的第三大原因。中风的治疗主要有两种方法，细胞疗法和药物疗法。我们建议将联合收割机和药物治疗相结合，以促进中风后神经功能的恢复。我们的初步数据表明，人脐带血细胞（HUCBCs）治疗中风改善功能的结果。亚治疗剂量的辛伐他汀与HUCBCs的组合增加了外源性给药的细胞迁移到缺血性脑中，并额外改善了中风后的治疗结果。因此，我们建议，HUCBC细胞为基础的治疗可以通过使组织更容易接受管理的细胞，通过创建一个微环境内的缺血性脑组织，促进基于细胞的诱导脑可塑性。本研究将使用临床相关的栓塞性大脑中动脉闭塞（MCAo）大鼠模型，这将为卒中恢复的新型治疗靶点提供新的重要数据。