CONTROL OF NT-3 EXPRESSION IN HIPPOCAMPUS

海马 NT-3 表达的控制

• 批准号: 2519884
• 负责人: ALISON J VIGERS
• 金额: $ 6.42万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-27 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519884
• 关键词: behavior disorders; beta galactosidase; cytokine; fibroblast growth factor; gene expression; genetically modified animals; glia; hippocampus; histochemistry /cytochemistry; immunocytochemistry; kainate; laboratory mouse; mutant; nerve injury; neural degeneration; neurons; neurotrophic factors; pilocarpine; prosencephalon; protein structure function; quinolinate; tissue /cell culture

Neurotrophins are key signaling molecules in the development and maintenance of the nervous system. This proposal describes research investigating the function of neurotrophin-3 (NT-3) in the mouse hippocampus and control of NT-3 expression following injury. Studies of expression will utilize a transgenic mouse having the lac Z gene targeted to the NT-3 locus, enabling the location and quantity of NT-3 expression to be easily determined through the use of specific beta- galactosidase substrates. Studies will be performed both in vivo and in vitro to determine the effects of seizure-inducing drugs such as quinolinic and kainic acids on NT-3 levels in distinct parts of the hippocampus and uncover any modulation of these NT-3 responses by specific cytokines and growth factors. Combined X-gal histochemistry and immunocytochemistry will be used to determine the cellular localization of altered NT-3 levels following seizure induction. The majority of transgenic mice lacking NT-3 die shortly after birth, making it impossible to identify the ultimate consequences of an absence of NT-3 in the CNS. Creation of a conditional NT-3 mutant using the cre- lox system is proposed. The goal of this project is to create mice lacking NT-3 only in the forebrain. These mice are expected to be viable and will be studied for alterations in CNS morphology and behavioral abnormalities. The potent neuronal survival-promoting effect of neurotrophins leads to the testable prediction that these mutant mice will be abnormally susceptible to seizure-induced neurodegeneration. Elucidation of the functions and regulation of NT-3 in the hippocampus promises to have important clinical and therapeutic implications for human conditions in which hippocampal neurons degenerate, such as epilepsy, stroke, CNS injury and Alzheimer's disease.

神经营养蛋白是发育中的关键信号分子 维护神经系统。该建议描述了研究 研究小鼠中神经营养蛋白3（NT-3）的功能 损伤后NT-3表达的海马和控制。研究 表达将利用具有LAC Z基因的转基因小鼠 针对NT-3基因座，使NT-3的位置和数量 表达可以通过使用特定β-轻松确定 半乳糖苷酶底物。研究将在体内和 体外确定癫痫发作的药物的作用，例如 NT-3水平的喹啉酸和海藻酸在不同部分的不同部分 海马并发现对这些NT-3响应的任何调节 特定的细胞因子和生长因子。 组合X-GAL组织化学 免疫细胞化学将用于确定细胞 癫痫发作后NT-3水平改变的定位。 大多数缺乏NT-3的转基因小鼠出生后不久死亡， 无法确定缺席的最终后果 中枢神经系统中的NT-3。使用CRE-创建条件NT-3突变体 提出了LOX系统。该项目的目的是创建老鼠 仅在前脑缺乏NT-3。这些老鼠有望可行 并将研究CNS形态和行为的改变 异常。有效的神经元生存促进作用 神经营养蛋白会导致这些突变小鼠的可检测预测 将异常容易受到癫痫发作的神经退行性的影响。 阐明海马中NT-3功能和调节 有望对 海马神经元退化的人类状况，例如 癫痫，中风，CNS损伤和阿尔茨海默氏病。