CELLULAR TOXICOLOGY OF THE DOPAMINE NEURON

多巴胺神经元的细胞毒理学

基本信息

批准号：
3083872
负责人：
JUAN R SANCHEZ-RAMOS
金额：
$ 5.83万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/3083872
关键词：
dopamine receptor drug adverse effect electron transport laboratory mouse laboratory rat methylphenyltetrahydropyridine mitochondria neural degeneration neurons neurotoxins tissue /cell culture

项目摘要

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.

候选人是研究行为药理学和临床研究的经验运动障碍训练。他的特殊利益包括药物使用的神经毒性后果。这里提出的研究涉及MPTP（L-甲基-4-苯基-1,2,3,6- 四氢吡啶），一种产生变化的米端类似物模仿灵长类动物和其他物种。尽管在理解的某些方面取得了进步药物引起神经元变性的机制，许多基本问题主要是由于复杂性而无法得到答复关于中枢神经系统的体内研究。一种方法解决这个问题是阐明MPTP在通过研究毒素对细胞培养的影响多巴胺能神经元和纹状体（或中脑）切片。这项研究的具体目的是：1）表征 MPTP和MPP+对毒性的选择性和不可逆性对培养中的多巴胺神经元，2）测试MPP+的假设主要作用于神经元纤维，随后逆行神经元的变性，3）检验以下假设。草自由基介导MPP+诱导的多巴胺神经元的破坏， 4）测试线粒体电子传输的假设在大鼠（或小鼠）纹状体和中脑中被MPP+抑制用扫描分光光度计测量的切片，5）进行测试靶组织（纹状体细胞）影响MPP+的假设神经毒性和促进多巴胺神经元从亚致死损伤。迈阿密大学神经病学系为开发临床提供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，医院神经病病房，学生和 Housestaff。