Neurotrophic Factor Gene Therapy for Brain Injury

描述（由申请人提供）：本申请的主要目的是 开始开发一种新的治疗创伤性脑损伤的方法- 用腺病毒载体进行神经营养因子基因治疗。虽然取得了巨大的进步， 在创伤性脑损伤的治疗中， 它可以防止和减少脑损伤后神经元的损失， 头部受伤的病人的长期残疾。动物研究 揭示了许多潜在的脑损伤治疗剂，然而，这些 化合物以全局方式施用，产生可能的副作用 对创伤患者的维持是有害的。基因疗法是一种 其将这些治疗剂长期地呈递到脑的特定区域， 大脑，使用基因工程病毒，没有重大的全球副作用。 为了发展创伤性脑损伤的基因治疗，必须考虑两个因素 解决：1）在受伤的脑组织中产生新的基因，诱导 通过腺病毒载体，必须证明，测量和优化， 大鼠和2）治疗性基因在动物模型中的神经保护能力 脑损伤的证据这些是具体目标的重点 这个提议。它们是：1）确定最佳病毒载体 浓度，将提供最大数量的受感染的脑细胞 当注射到正常的， 损伤的皮质，2）检查病毒介导的神经保护作用， 胶质细胞源性神经营养因子（GDNF）或脑源性 皮质神经营养因子（BDNF）的表达 挫伤，和3）探讨是否病毒介导的神经营养因子 （GDNF或BDNF）在皮质挫伤后注射可以挽救和 保护神经元和行为功能。此外，该提案将 测量受损皮质组织中的转基因表达。所有这些 研究将为进一步研究基因治疗建立一个框架， 创伤性脑损伤未来的问题将涉及治疗窗口 机会，长期行为和认知功能，以及 脑外伤治疗新基因和病毒载体的优化 损伤此外，这些研究将提供一个全面的 神经生物学领域的本科生研究培训计划， 分子生物学和动物行为学。

DESCRIPTION (provided by applicant): The main objective of this application is to begin to develop a new therapeutic approach for traumatic brain injury - neurotrophic factor gene therapy with adenoviral vectors. While great strides have been made in the management of traumatic brain injury, no treatments exist which prevent and minimize neuronal loss following brain injury, the main cause of long-term disabilities in head-injured patients. Animal studies have revealed many potential therapeutic agents for brain injury, however, these compounds are administered in a global manner, producing possible side effects detrimental to the maintenance of the trauma patient. Gene therapy is a way in which to chronically present these therapeutic agents to a specific area of the brain, using genetically engineered viruses, without major global side effects. In order to develop gene therapy for traumatic brain injury, two factors must be addressed: 1) the production of novel genes in injured brain tissue, induced by an adenoviral vector, must be demonstrated, measured, and optimized in the rat and 2) the neuroprotective ability of a therapeutic gene in an animal model of brain injury must be demonstrated. These are the focus of the specific aims of this proposal. They are: 1) to determine the optimal viral vector concentration that will provide the greatest number of infected brain cells with minimal amounts of neural toxicity when injected into the normal and injured cortex, 2) to examine the neuroprotective effects of virally mediated glial cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF) expression in the cortex following a cortical contusion, and 3) to explore whether a virally mediated neurotrophic factor (either GDNF or BDNF) injected after a cortical contusion can rescue and protect neurons and behavioral function. In addition, this proposal will measure transgene expression in compromised cortical tissue. Together, these studies will develop a framework for further investigations of gene therapy for traumatic brain injury. Future questions will address the therapeutic windows of opportunity, long-term behavioral and cognitive function, and the optimization of new therapeutic genes and viral vectors for traumatic brain injury. In addition, these studies will provide a comprehensive research-training program for undergraduates in the fields of neurobiology, molecular biology, and animal behavior.