SIGNAL TRANSDUCTION MECHANISMS IN GLUTAMATE TOXICITY

谷氨酸毒性的信号转导机制

• 批准号: 2241119
• 负责人: DEAN M HARTLEY
• 金额: $ 2.27万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2241119
• 关键词: Alzheimer's disease; Huntington's disease; biological signal transduction; calmodulin dependent protein kinase; cytolysis; gene therapy; glutamates; laboratory mouse; molecular genetics; neurons; neurotoxins; protein kinase C; stroke; tissue /cell culture; transfection /expression vector

The etiology of certain acute insults and chronic neuro-degenerative disorders has been advanced by the finding that these diseases are possibly manifested fully or in part through glutamate receptor activation. These diseases include stroke, Alzheimer's and Huntington's disease. Unfortunately, very little is known about the intracellular mechanisms responsible for glutamate-induced cell death. The power of molecular genetics will be used to probe signal transduction mechanisms. The catalytic or regulatory (inhibitory) domain of protein kinase C, calcium/calmodulin-dependent protein kinase II, and calcium activated neutral proteinase will be expressed in cultured neurons using a HSV-1 vector system. Infected cells will then be challenged with toxic doses of various glutamate agonists to determine the role of these enzymes in mediating neuronal death. The development of the HSV-1 vector system to study glutamate neurotoxicity could have broad implications: 1) An understanding of these intracellular processes may suggest clinical therapeutic strategies for stroke. 2) The HSV-1 vector may provide a novel therapeutic approach in treating chronic neurologic disorders by restoring function through gene therapy.

某些急性损伤和慢性神经退行性病变的病因 这些疾病可能是 全部或部分通过谷氨酸受体激活表现出来。 这些 这些疾病包括中风、阿尔茨海默氏症和亨廷顿氏病。 不幸的是，人们对细胞内机制知之甚少， 负责谷氨酸诱导的细胞死亡。 分子的力量 遗传学将用于探测信号转导机制。 的 蛋白激酶C的催化或调节（抑制）结构域， 钙/钙调蛋白依赖性蛋白激酶II和钙激活的 中性蛋白酶将使用HSV-1在培养的神经元中表达 向量系统 感染的细胞将受到毒性剂量的 各种谷氨酸激动剂以确定这些酶在 介导神经元死亡。 HSV-1载体系统的开发， 研究谷氨酸神经毒性可能具有广泛的意义：1） 对这些细胞内过程的理解可能提示临床 中风的治疗策略 2)HSV-1载体可以提供一种新的 通过恢复治疗慢性神经系统疾病的治疗方法 通过基因治疗发挥作用。