RESTORATION OF DOPAMINE FUNCTION IN PARKINSON'S DISEASE

GDNF对中脑多巴胺(DA)神经元的神经修复和神经保护作用为帕金森病的治疗提供了一条新的途径。与许多趋向性因子一样，这种趋性因子的最佳成功依赖于蛋白质的集中和受控传递，以影响DA神经元的功能，而不会产生不想要的副作用。我们的中心假设是，与其他给药方法相比，慢性脑室或壳核内GDNF对受损的DA神经元具有更高的疗效、效力和更少的副作用。1.我们建议使用一种新型的留置泵，在自由活动的MPTP损伤猴体内长期输送GDNF，以评估两个输送部位：侧脑室和壳核。2.我们还将研究GDNF在两种输注模式中的洗脱和营养因子的重新表达。不同的高度集成的项目和核心将提供有关慢性GDNF治疗对DA神经元的功能影响的关键数据，并为帕金森病卓越中心奠定基础。项目1将使用微透析、体内电化学和死后高效液相-电化学法来研究单侧MPTP损伤的猴子在接受GDNF慢性输注后的黑质纹状体通路。项目2将研究注射GDNF的行为后果，并使用fMRI方法研究DA神经元潜在的功能变化。项目3将对长期接受治疗的同一组猴子的多巴胺能神经元进行轨迹追踪和免疫组织化学测量。核心A-D都将为项目1-3中的实验大纲提供必要的支持。这些研究将回答有关营养因子在自由活动和行为正常的恒河猴体内的慢性传递的关键问题。这些数据可能为利用营养分子治疗人类帕金森氏症奠定基础。

The neuroestorative and neuroprotective tropic actions of GDNF on midbrain dopamine (DA) neurons provide a promising therapeutic approach for the treatment of Parkinson's disease. As with many tropic factors, optimum success of this tropic factor depends on focal and controlled delivery of the protein to affect the function of DA neurons, without producing unwanted side effects. It is our central hypothesis that chronic intracerebroventricular or intraputamenal GDNF willproduce effects on damaged DA neurons with greater efficacy, potency and reduced side effects as compared to other methods of delivery. 1. We propose to use a novel indwelling pump that can deliver GDNF chronically in the freely-moving MPTP-lesioned monkey to evaluate two sites of delivery: the lateral ventricle and the putamen. 2. We will also investigate washout of GDNF and re-instatement of the trophic factor in both infusion paradigms. The different highly integrated Projects and Cores will provide key data regarding the functional effects of chronic GDNF treatments to DA neurons, and form the foundation for a Parkinson's Disease Center of Excellence. Project 1 will use microdialysis, in vivo electrochemistry and postmortem HPLC-EC methods to study the nigrostriatal pathway of unilateral MPTP-lesioned monkeys that have received chronic infusions of GDNF. Project 2 will investigate the behavioral consequences of the GDNF infusions and study potential functional changes to DA neurons using fMRI methods. Project 3 will carryout tract tracing and immunohistochemical measures of DA neurons in the same groups of chronically treated monkeys. The Cores A-D will all provide needed support for the experiments outline in Projects 1-3. These studies will answer key questions regarding the chronic delivery of a trophic factor in freely-moving and behaving rhesus monkeys. Such data could lay the foundation for the use of trophic molecules for the treatment of Parkinson's disease in humans.