CELLULAR TOXICOLOGY OF THE DOPAMINE NEURON

多巴胺神经元的细胞毒理学

• 批准号: 3083871
• 负责人: JUAN R SANCHEZ-RAMOS
• 金额: $ 7.58万
• 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/3083871
• 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.

候选人是一名药理学家和神经学家，从事研究 行为药理学和临床研究经验 关于运动障碍的训练。他的特殊利益包括 锥体外系综合征和药物使用的神经毒性后果。 本文涉及MPTP(L-甲基-4-苯基-1，2，3，6- 四氢吡啶)，一种能产生变化的度冷丁类似物 在灵长类动物和其他动物身上模拟帕金森氏病的损害 物种。尽管在理解某些方面取得了进展，但 该药物导致神经元变性的机制，许多 基本问题仍然没有得到回答，主要是因为 对中枢神经系统的活体研究。一种方法 对此问题的研究旨在阐明MPTP的作用机制。 通过研究毒素对细胞培养的影响进行体外实验。 多巴胺能神经元和纹状体(或中脑)脑片上。 这项研究的具体目的是：1)表征 MPTP和MPP+毒性的选择性和不可逆性 培养中的多巴胺神经元，2)检验MPP+ 主要作用于神经纤维，随后逆行 神经元的退化，3)检验假设 氧自由基介导MPP+对多巴胺神经元的破坏 4)检验线粒体电子传递的假设 在大鼠(或小鼠)纹状体和中脑被MPP+抑制 用扫描分光光度计测量切片，以及5)测试 靶组织(纹状体细胞)影响MPP+的假说 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 为临床开发提供出色的资源 调查员：设备齐全的实验室，基础研究人员， 门诊、医院神经科病房、学生和 家政人员。