Blood-Brain Barrier Repair in Cell Therapy for Stroke

中风细胞疗法中的血脑屏障修复

基本信息

批准号：
8490459
负责人：
CESARIO V BORLONGAN
金额：
$ 41.66万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8490459
关键词：
Acute Adverse effects Alteplase Animal Model Animals Area Arteries Attenuated Binding Blood - brain barrier anatomy Blood Vessels Bone Marrow Brain Brain Edema CXCR4 gene Cell Therapy Cells Chronic Clinic Data Deposition Endothelium Event Extracellular Matrix Degradation Extravasation FDA approved Goals Homeostasis Homing Hour Human Injury Intravenous Ischemic Stroke Laboratories Matrix Metalloproteinases Natural regeneration Neuraxis Neuronal Injury Neurons Outcome Patients Peripheral Pharmaceutical Preparations Phase Phenotype Plasminogen Activator Population Process Recovery of Function Recruitment Activity Reperfusion Therapy Research Design Role Serine Protease Serum Proteins Signal Pathway Site Staging Stem cell transplant Stem cells Stroke Stromal Cell-Derived Factor 1 Technology Testing Therapeutic Translating Transplantation Treatment Protocols Vascular Endothelial Growth Factors Vascular remodeling acute stroke angiogenesis axon regeneration base brain tissue cell motility chemokine receptor clinical application design improved injured intravenous administration neglect nervous system disorder neurogenesis neurotoxicity novel novel strategies prevent reconstitution regenerative repaired restoration stem stroke therapy

项目摘要

DESCRIPTION (provided by applicant): The present proposal advances the motto "you break it, we repair it". Recognizing that blood-brain barrier (BBB) breakdown could negatively influence central nervous system (CNS) regenerative processes after stroke, we propose to structurally and functionally restore the BBB in an acute and sub-acute stroke setting. Our preliminary data demonstrate that intravenous administration of a heterogeneous cell population containing stem or progenitor cells shows benefit in animal models of stroke. More recently, we are able to ascribe the functional recovery in transplanted stroke animals to the presence of endothelial progenitor cells (EPC) in the grafted cell population. Whereas cell-based technologies are largely designed to circumvent the BBB for delivery of cells or drugs from the periphery into the brain, we are taking here a novel approach of repairing the BBB damage in stroke. We are also cognizant that the treatment of ischemic stroke is limited to the serine protease tissue-type plasminogen activator (tPA). However, less than 3 percent of ischemic stroke patients benefit from tPA treatment, due to the drug's narrow 3-hour therapeutic window and its detrimental side effects in particular the drug's exacerbation of stroke-induced BBB damage. That 1) stroke is accompanied by BBB damage, 2) tPA adversely contributes to this BBB damage, and 3) cell therapy can afford BBB repair, form the basis of our overarching hypothesis. We posit that any treatment regimen directed at attenuating stroke deficits should consider the pivotal role of BBB repair in order to maintain CNS homeostasis and enhance neuronal regeneration. A regenerative mechanism involving the repair of the damaged BBB by EPC is critical to the successful outcome of cell therapy in stroke, and should also extend the therapeutic window, as well as improve the functional benefits of tPA treatment in stroke.

描述（由申请人提供）：本提案推进了座右铭：“您打破它，我们修复它”。认识到血脑屏障（BBB）的崩溃可能会对中风后的中枢神经系统（CNS）负面影响，因此我们建议在结构和功能上恢复BBB的急性和亚急性中风设置。我们的初步数据表明，含有茎或祖细胞的异质细胞群静脉内给药显示中风动物模型中有益。最近，我们能够将移植中风动物中的功能恢复归因于移植细胞群中内皮祖细胞（EPC）的存在。尽管基于细胞的技术在很大程度上旨在规避BBB以从外围传递细胞或药物进入大脑，但我们正在采用一种新的修复中风中BBB损害的方法。我们还认识到缺血性中风的治疗仅限于丝氨酸蛋白酶组织型纤溶酶原激活剂（TPA）。但是，由于药物的3小时治疗窗口较窄，尤其是该药物加剧了中风引起的BBB损伤，因此不到3％的缺血性中风患者受益于TPA治疗。 1）中风伴有BBB损伤，2）TPA对这种BBB损害有不利的贡献，3）细胞疗法可以负担BBB修复，这是我们总体假设的基础。我们认为，任何针对衰减中风缺陷的治疗方案都应考虑BBB修复的关键作用，以维持CNS稳态并增强神经元再生。 EPC修复损坏的BBB的再生机制对于中风中细胞治疗的成功结果至关重要，还应扩展治疗窗口，并提高中风中TPA治疗的功能益处。