Cord Blood is Neuroprotective in a Rat Model of Stroke

脐带血对中风大鼠模型具有神经保护作用

• 批准号: 7394055
• 负责人: ALISON E WILLING
• 金额: $ 9.26万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394055
• 关键词: Address; Adverse effects; Affect; Aftercare; Age; Alteplase; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Appendix; Astrocytes; B-Lymphocytes; Behavioral; Binding; Biological Assay; Blood Cells; Brain; Brain Injuries; Cell Death; Cell Fraction; Cell Separation; Cell Therapy; Cell Transplantation; Cells; Cerebrovascular Disorders; Cessation of life; Chloride Ion; Chlorides; Clinical; Condition; Cultured Cells; DNA Binding; Disease; End Point; Flow Cytometry; Gene Expression; Genes; Genetic; Goals; Hour; Human; Hypoxia; Immune; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro; Infarction; Infiltration; Inflammation; Inflammatory Response; Inflammatory Response Pathway; Injection of therapeutic agent; Injury; Label; Localized; Measures; Mediating; Microarray Analysis; Microglia; Middle Cerebral Artery Infarction; Middle Cerebral Artery Occlusion; Modeling; Mononuclear; Morbidity - disease rate; Motor; NF-kappa B; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oligodendroglia; Outcome Measure; Pathology; Performance; Peripheral; Population; Population Heterogeneity; Rattus; Recovery; Reporting; Research; Series; Signal Transduction; Site; Staining method; Stains; Standards of Weights and Measures; Stem cells; Stroke; T-Lymphocyte; Testing; Tetrazolium; Time; Transplantation; Umbilical Cord Blood; Umbilical cord structure; United States; Western Blotting; artery occlusion; blood treatment; cell type; cytokine; day; disability; improved; innovation; monocyte; mortality; neuronal survival; neuroprotection; programs; relating to nervous system; repaired; research study; response; stroke recovery; therapy development

Cerebrovascular disease is the third leading cause of morbidity and mortality in the United States. As the population ages, it will be even more pressing to develop effective treatment options that can not only increase survival, but decrease disability. In a rat model of stroke (the middle cerebral artery occlusion or MCAO) we found that intravenously (iv) administering the mononuclear fraction from human umbilical cord blood (HUCB) enhances motor functions. In this proposal we will explore how the administration of this population of cells may induce recovery and decrease anatomical damage induced by MCAO through direct neuroprotective and anti-inflammatory mechanisms. In Aim 1we will characterize how iv HUCB cells modify the underlying pathology and inflammation of the MCAO when administered 24 hours to 7 days after the MCAO using markers of inflammation, neuronal death, neurosurvival, and apoptosis. In Aim 2, we will identify the specific subpopulation of the HUCB cells that is instrumental in inducing behavioral and anatomical recovery. This will be accomplished using fluorescent activated cell sorting (FACS) to enrich T cell, B Cell, monocyte and "stem" cell fractions for transplantation into a stroked rat. Endpoint measures in these studies will include performance on a battery of motor tests and infarct volume. Aim 3 proposes a series of in vitro studies to examine whether the HUCB cells modify the inflammatory response to the MCAO through direct interactions with neural cell popultions. Cell culture assays using neuronal, astrocytic, oligodendrocytes or microglia will be conducted to identify direct interactions and the molecular signals that mediate survival, cytokine expression and NF-kappaB binding activity in response to hypoxia/reoxygenation. In Aim 4 we will use microarray technology to identify neural repair/survival genes that are up-regulated by HUCB treatment of neuronal cultures. All microarray experiments will be verified with western blots and immunohistochemistry. The studies proposed here will increase our understanding of the neuroprotective and anti-inflammatory mechanisms underlying the recovery from stroke induced by HUCB cell transplantation and may also identify other potential targets in stroke for development of treatment options. The ultimate goal of this research program is to develop an innovative HUCB cell based therapy into a viable clinical option for transplantation in neurodegenerative disease and brain injury.

脑血管疾病是美国发病率和死亡率的第三主要原因。作为 人口年龄，开发有效的治疗选择将更加紧迫，不仅可以 增加生存率，但会降低残疾。在中风的大鼠模型中（中大脑中动脉阻塞或 MCAO）我们发现静脉内（IV）从人脐带施用单核分数 血液（HUCB）增强运动功能。在此提案中，我们将探讨如何管理此事 细胞的种群可能引起MCAO通过直接引起的恢复并减少解剖学损害 神经保护和抗炎机制。在AIM 1中将表征IV HUCB细胞的表征 修改MCAO的潜在病理和炎症，当时24小时至7天给药 使用炎症，神经元死亡，神经存在和凋亡的MCAO。在AIM 2中，我们将 确定在诱导行为和 解剖学恢复。这将使用荧光激活的细胞分选（FACS）来富集T 细胞，B细胞，单核细胞和“干式”细胞馏分，用于移植到抚摸大鼠中。终点测量 这些研究将包括在一系列运动测试和梗塞量上的性能。 AIM 3提出 一系列体外研究，以检查HUCB细胞是否改变了对MCAO的炎症反应 通过直接与神经细胞p的相互作用。使用神经元，星形细胞， 将进行少突胶质细胞或小胶质细胞，以鉴定直接相互作用和分子信号 介导对低氧/重氧的响应，介导生存率，细胞因子表达和NF-kappab结合活性。 在AIM 4中，我们将使用微阵列技术来识别被上调的神经修复/生存基因 HUCB治疗神经元培养物。所有微阵列实验将通过Western印迹进行验证， 免疫组织化学。这里提出的研究将增加我们对神经保护的理解 和抗炎机制，从HUCB细胞引起的中风恢复的基础 移植，还可以识别中风中的其他潜在靶标，以开发治疗选择。 该研究计划的最终目的是将基于HUCB细胞的创新疗法开发到 神经退行性疾病和脑损伤中移植的可行临床选择。