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）：本提案提出了“你打破它，我们修复它”的座右铭。认识到血脑屏障 (BBB) 破坏可能会对中风后中枢神经系统 (CNS) 的再生过程产生负面影响，我们建议在急性和亚急性中风环境中从结构和功能上恢复 BBB。我们的初步数据表明，静脉注射含有干细胞或祖细胞的异质细胞群在中风动物模型中显示出益处。最近，我们能够将移植中风动物的功能恢复归因于移植细胞群中内皮祖细胞（EPC）的存在。虽然基于细胞的技术主要是为了绕过血脑屏障将细胞或药物从外周输送到大脑，但我们在这里采用了一种修复中风中血脑屏障损伤的新方法。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）。然而，只有不到 3% 的缺血性中风患者从 tPA 治疗中受益，因为该药物的 3 小时治疗窗较窄，且具有有害的副作用，特别是该药物会加剧中风引起的 BBB 损伤。 1) 中风伴随着 BBB 损伤，2) tPA 会对这种 BBB 损伤产生不利影响，3) 细胞疗法可以修复 BBB，构成了我们总体假设的基础。我们认为任何旨在减轻中风缺陷的治疗方案都应考虑血脑屏障修复的关键作用，以维持中枢神经系统稳态并增强神经元再生。涉及通过 EPC 修复受损 BBB 的再生机制对于中风细胞疗法的成功至关重要，并且还应该延长治疗窗口，并提高 tPA 治疗中风的功能益处。