Enhanced cellular therapy for neonatal stroke

新生儿中风的增强细胞疗法

• 批准号: 10055777
• 负责人: Fernando Francisco Gonzalez
• 金额: $ 35.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2022-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055777
• 关键词: Adult; Angiogenic Factor; Angiopoietin-2; Apoptosis; Blood Vessels; Brain; Brain Injuries; Brain region; Brain-Derived Neurotrophic Factor; Cause of Death; Cell Communication; Cell Count; Cell Death; Cell Proliferation; Cell Therapy; Cell Transplantation; Cells; Central Nervous System Diseases; Cognitive; Development; Diagnosis; Disease; Endothelial Cells; Environment; Erythropoietin; Exposure to; Functional disorder; Genetic; Goals; Growth; Growth Factor; Growth Factor Receptors; Histologic; Histology; Infarction; Inflammation; Injury; Intervention; Ischemia; Ischemic Brain Injury; KDR gene; Knowledge; Lesion; Life; Maps; Measures; Mesenchymal Stem Cells; Modality; Modeling; Modification; Natural regeneration; Necrosis; Neonatal; Neurons; Newborn Infant; Outcome; Oxidative Stress; PIK3CG gene; Pathway interactions; Play; Predisposition; Process; Rattus; Reperfusion Injury; Reperfusion Therapy; Rodent; Role; Signal Pathway; Stroke; Survivors; Techniques; Testing; Therapeutic; Time; Vascular Endothelial Growth Factors; Vascular remodeling; Western Blotting; angiogenesis; behavioral outcome; brain volume; density; disability; excitotoxicity; functional improvement; functional outcomes; improved; improved outcome; ischemic injury; migration; morphogens; mortality; motor function improvement; neonatal stroke; neonate; nerve stem cell; neurogenesis; neuron loss; neurovascular; neurovascular unit; novel therapeutic intervention; paracrine; perinatal stroke; public health relevance; release factor; repaired; response; response to brain injury; response to injury; scaffold; socioeconomics; stem cell therapy

PROJECT SUMMARY Neonatal stroke is an important cause of death and disability, resulting from multiple pathways of cell death and dysfunction that evolve over a prolonged period of time. There is insufficient knowledge regarding the role of angiogenesis in the response to focal ischemia-reperfusion injury that is the most common cause of early stroke. Angiogenesis and neuronal repopulation occur in close proximity, with paracrine factors supporting neuron-endothelial cell interactions that are critical for repair. Modulating this neurovascular niche may be a potential target for enhancing outcomes after ischemic brain injury in the newborn period. Cell-based therapies have emerged as a promising treatment for CNS disease, although the mechanism of repair has been controversial. Mesenchymal stem cells (MSC) play a role in vascular formation and secrete pro-angiogenic factors, express a number of growth factor receptors, and may preferentially differentiate into cells capable of building new blood vessels after injury. MSC treatment has been shown to improve histological and functional outcomes after ischemic injury, even when therapy was delayed, but it is only partially reparative. Modifying MSC in a way that enhances effects on the neurovascular unit may provide additional benefit. Our overall objective is to determine the mechanism of regeneration and repair with delayed cellular therapy for neonatal stroke by focusing on the vascular response in the injured brain. In Aim 1, we will test the hypothesis that MSC pre-exposed to EPO will enhance angiogenesis and vascular remodeling following neonatal focal ischemia-reperfusion injury in the rat more than MSC or EPO therapy alone. In Aim 2, we will clarify to what extent this modified cellular therapy modulates long-term repair by using a number of techniques to quantify cell fate, gross histology and long-term sensorimotor and cognitive outcomes. Finally, in Aim 3, we will define the roles of specific downstream signaling pathways on angiogenesis and repair following ischemia- reperfusion injury and cellular therapy. This will determine critical, modifiable pathways important for angiogenesis in the developing brain and following focal injury, which can be further studied to enhance long- term repair. Our primary hypothesis is that delayed treatment with MSC pretreated with EPO will promote vascular growth and remodeling, increase neurogenesis, and improve long-term histological and functional outcomes after neonatal stroke. This will provide a late treatment option for a common cause of early brain injury, where diagnosis is often delayed.

项目概要 新生儿中风是死亡和残疾的重要原因，由多种细胞死亡途径引起 以及长期发展的功能障碍。对角色认识不足 血管生成对局灶性缺血再灌注损伤的反应，这是早期血管生成的最常见原因 中风。血管生成和神经元再生非常接近地发生，旁分泌因子支持 神经元-内皮细胞相互作用对于修复至关重要。调节这种神经血管生态位可能是 改善新生儿期缺血性脑损伤后预后的潜在目标。基于细胞的疗法 尽管修复机制尚未明确，但已成为治疗中枢神经系统疾病的一种有前景的方法 有争议的。间充质干细胞 (MSC) 在血管形成中发挥作用并分泌促血管生成 因子，表达许多生长因子受体，并可能优先分化成能够 受伤后建立新血管。 MSC 治疗已被证明可以改善组织学和功能 缺血性损伤后的结果，即使治疗被延迟，但也只是部分修复。修改 间充质干细胞以增强对神经血管单位的作用的方式可能会提供额外的益处。 我们的总体目标是确定延迟细胞疗法的再生和修复机制 通过关注受伤大脑的血管反应来治疗新生儿中风。在目标 1 中，我们将测试 假设 MSC 预先暴露于 EPO 将增强血管生成和血管重塑 新生大鼠局灶性缺血再灌注损伤比单独使用MSC或EPO治疗更严重。在目标 2 中，我们将 通过使用多种技术阐明这种改良的细胞疗法在多大程度上调节长期修复 量化细胞命运、大体组织学以及长期感觉运动和认知结果。最后，在目标 3 中，我们 将定义特定下游信号通路对缺血后血管生成和修复的作用 再灌注损伤和细胞治疗。这将确定关键的、可修改的途径，对于 发育中的大脑和局灶性损伤后的血管生成，可以进一步研究以增强长期 期限修复。我们的主要假设是，用 EPO 预处理的 MSC 延迟治疗将促进 血管生长和重塑，增加神经发生，改善长期组织学和功能 新生儿卒中后的结果。这将为早期大脑的常见原因提供晚期治疗选择 损伤，诊断常常被延误。