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. .

描述：创伤性脑损伤 (TBI) 通常由年轻人和老年人的机动车损伤和跌倒引起，每年影响美国近 170 万人。在美国，TBI 不仅是儿童和年轻人死亡的主要原因，也是造成永久性残疾的主要原因。目前 TBI 尚无治愈方法，主要措施是尽量减少因初始损伤引发的血压变化、脑肿胀或颅内压变化而造成的继发性损伤。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 将基因导入大脑中的神经祖细胞，然后利用该技术指导损伤后的皮质神经发生。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向大脑神经祖细胞的转移，从而能够递送编码成纤维细胞生长因子-2和神经生成素2的基因，这些蛋白质被证明可以增强神经发生并指导神经祖细胞的形成。分别是神经元分化。我们将在 TBI 动物模型中评估诱导迁移和增加神经元整合是否可以通过组织学、认知评估和运动评估相结合来导致功能改善。 。