Ultrasound-aided gene transfer to direct cortical neurogenesis after brain injury

超声辅助基因转移至脑损伤后直接皮质神经发生

• 批准号: 8722168
• 负责人: Philip J Horner
• 金额: $ 40.49万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722168
• 关键词: Adult; Adverse effects; Animal Model; Behavioral; Biological Assay; Bioluminescence; Blood Pressure; Brain; Brain Edema; Brain Injuries; Cause of Death; Cell Proliferation; Cells; Charge; Child; Clinical Trials; Cognitive; Development; Drug Formulations; Elderly; Emotional; Enzyme-Linked Immunosorbent Assay; Ependymal Cell; Evaluation; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Focused Ultrasound Therapy; Frequencies; Gene Delivery; Gene Transfer; Genes; Goals; Healed; Hemolysis; Histology; Image; Immunofluorescence Immunologic; Immunohistochemistry; Injury; Intervention; Intracranial Pressure; Intraventricular Injections; Kinetics; Label; Lead; Lesion; Lipids; Magnetic Resonance Imaging; Mammals; Mediating; Medical; Membrane; Methods; Microbubbles; Modeling; Monitor; Motor; Neuroglia; Neuronal Differentiation; Neurons; Nucleic Acids; Outcome; Pathway interactions; Patients; Peptides; Polymers; Production; Proteins; Rattus; Recovery; Reporter Genes; Risk; Rodent Model; Site; Specificity; Stem cells; Stream; Structure of choroid plexus; Surface; System; Technology; Testing; Therapeutic; Transfection; Traumatic Brain Injury; Ultrasonography; United States; Work; cell type; cognitive recovery; disability; falls; functional improvement; healing; high risk; improved; improved functioning; in vitro Model; in vitro testing; in vivo; innovation; light scattering; migration; motor vehicle injury; nerve stem cell; neurogenesis; polymerization; public health relevance; relating to nervous system; repaired; response; stem; subventricular zone; therapeutic gene; transcription factor; transgene expression; vector; young adult

DESCRIPTION: Traumatic brain injury (TBI), commonly caused by motor vehicle injury and falls in the young and elderly, afflicts nearly 1.7 million people in the United States each year. n addition to being a leading cause of death in children and young adults, TBI is also a major cause of permanent disability in the United States. There are currently no curative treatments for TBI, and the main course of action is to minimize secondary damage that results from changes in blood pressure, brain swelling, or intracranial pressure that is triggered by the initia injury. The overall goal of this project is to first develop a well-tolerated means of transferring genes to neural progenitor cells in the brain and then to use this technology to direct cortical neurogenesis after injury. We propose to use focused ultrasound to enhance non-viral gene transfer to neural progenitor cells in the brain mediated by a targeted polymer delivery vector, thus enabling the delivery of genes encoding fibroblast growth factor-2 and neurogenin2, proteins shown to enhance neurogenesis and direct neuron differentiation, respectively. We will evaluate in an animal model of TBI whether induced migration and increased neuronal integration can lead to functional improvement through a combination of histology, cognitive evaluations, and motor assessments. .

产品说明：创伤性脑损伤（TBI），通常由机动车损伤和年轻人和老年人的福尔斯跌倒引起，每年折磨着美国近170万人。除了是儿童和年轻人死亡的主要原因外，TBI也是美国永久性残疾的主要原因。目前还没有针对TBI的治愈性治疗，并且主要的行动过程是最小化由初始损伤触发的血压、脑肿胀或颅内压变化引起的继发性损伤。该项目的总体目标是首先开发一种耐受性良好的转移手段， 基因到大脑中的神经祖细胞，然后使用这种技术来指导受伤后的皮层神经发生。我们建议使用聚焦超声来增强由靶向聚合物递送载体介导的非病毒基因转移到大脑中的神经祖细胞，从而实现编码成纤维细胞生长因子-2和neurogenin 2的基因的递送，这两种蛋白质被证明可以增强神经发生并分别指导神经元分化。我们将通过组织学、认知评估和运动评估的组合，在TBI动物模型中评估诱导的迁移和增加的神经元整合是否可以导致功能改善。.