CELLULAR TOXICOLOGY OF THE DOPAMINE NEURON

多巴胺神经元的细胞毒理学

• 批准号: 3083870
• 负责人: JUAN R SANCHEZ-RAMOS
• 金额: $ 6.61万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1991-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3083870
• 关键词: dopamine receptor; drug adverse effect; electron transport; laboratory mouse; laboratory rat; methylphenyltetrahydropyridine; mitochondria; neural degeneration; neurons; neurotoxins; tissue /cell culture

The candidate is a pharmacologist and neurologist with research experience in behavioral pharmacology and clinical research training in movement disorders. His-special interests include extrapyramidal syndromes and neurotoxic consequences of drug use. Research proposed here concerns MPTP (l-methyl-4-phenyl-1,2,3,6- tetrahydropyridine), a meperidine analogue which produces changes that mimic the lesion of Parkinson's disease in primates and other species. Despite advances in understanding some aspects of the mechanism by which the drug causes neuronal degeneration, many basic questions remain unanswered due primarily to the complexity of in vivo research on the central nervous system. One approach to this problem is to elucidate the mechanism of action of MPTP in vitro by studying the effects of the toxin on cell cultures of dopaminergic neurons and upon striatal (or midbrain) slices. Specific aims of this research are: 1) to characterize the selectivity and irreversibility of MPTP and MPP+ toxicity towards dopamine neurons in culture, 2) to test the hypothesis that MPP+ acts primarily on neuronal fibers, with subsequent retrograde degeneration of the neuron, 3) to test the hypothesis that oxyradicals mediate MPP+ induced destruction of dopamine neurons, 4) to test the hypothesis that mitochondrial electron transport is inhibited by MPP+ in rat (or mouse) striatal and midbrain slices as measured with scanning spectrophotometer, and 5) to test the hypothesis that target tissue (striatal cells) influences MPP+ neurotoxicity and facilitates recovery of dopamine neurons from sub-lethal damage. The University of Miami Dept of Neurology provides outstanding resources for development of a clinical investigator: fully equipped laboratories, basic research staff, out-patient clinics, hospital neurology ward, students and housestaff.

候选人是药理学家和神经学家， 行为药理学和临床研究经验 运动障碍训练。 他的特殊兴趣包括 锥体外系综合征和吸毒的神经毒性后果。 本文提出的研究涉及MPTP（1-甲基-4-苯基-1，2，3，6-三氟甲基）， 四氢吡啶），一种哌替啶类似物， 在灵长类动物和其他动物中模拟帕金森病的病变， 物种 尽管在理解某些方面取得了进展， 药物引起神经元变性的机制，许多 基本问题仍然没有答案，主要是由于复杂性， 对中枢神经系统的活体研究。 一种方法 解决这个问题的方法是阐明MPTP的作用机制， 通过研究毒素对细胞培养物的影响， 多巴胺能神经元和纹状体（或中脑）切片。 本研究的具体目的是：1）表征 MPTP和MPP+毒性的选择性和不可逆性 培养的多巴胺神经元，2）为了检验MPP+ 主要作用于神经纤维，随后逆行 神经元的退化，3）为了检验假设， 氧自由基介导MPP+诱导的多巴胺神经元的破坏， 4)来验证线粒体电子传递 在大鼠（或小鼠）纹状体和中脑中被MPP+抑制 用扫描分光光度计测量切片，和5）测试 假设靶组织（纹状体细胞）影响MPP+ 神经毒性和促进多巴胺神经元的恢复， 亚致命伤害 迈阿密大学神经病学系 为临床开发提供了出色的资源 研究人员：设备齐全的实验室，基础研究人员， 门诊诊所、医院神经科病房、学生和 管家