Nigral targeting strategies for neural function restora

神经功能恢复的黑质靶向策略

• 批准号: 6824647
• 负责人: JOHN RICHARD SLADEK
• 金额: $ 30.66万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6824647
• 关键词: Cercopithecidae; Parkinson's disease; brain mapping; brain morphology; cell population study; confocal scanning microscopy; corpus striatum; disease /disorder model; dopamine; electron microscopy; embryo /fetus tissue transplantation; functional ability; histology; longitudinal animal study; nervous system transplantation; neurons; neurotrophic factors; nonhuman therapy evaluation; substantia nigra

PROJECT 3. NIGRAL TARGETING STRATEGIES FOR RESTORATION OF NEURAL FUNCTION Although intrastriatal grafts of embryonic DA neurons survive, send neurites into the host brain, elevate DA levels in the vicinity of the grafts, and restore motor function in parkinsonian MPTP-treated monkeys, the functional benefits in humans have been variable, somewhat limited and sometimes associated with dyskinesia. These limitations may be due to the ectopic placement of grafts in the striatum and the resulting dysregutated release of dopamine. Recent studies have shown the feasibility of grafting embryonic substantia nigra (SN) into the host SN and grafts of embryonic striatum into the striatum, which can be used to promote directed fiber outgrowth from DA-containing neurites towards appropriate targets. The experiments proposed build upon this knowledge. The hypothesis is that co-grafting embryonic striatum into the striatum and ventral mesencephalic tissue adjacent to the substantia nigra will improve recovery, since replacement nigral cells can be regulated in the nigra and provide appropriate release of dopamine in the normal target areas. Behavioral measures will assess functional recovery, immunohistochemical markers for DA neurons will be used as indices of graft survival in the target regions, and biochemical effects will be determined. Confocal and electron microscopy will aid the depiction of circuit reconstruction that may result from co-grafts. Prior to sacrifice, the retrograde tracer fluorogold wilt be injected in the caudate or putamen to determine if grafted dopaminergic neurons in the nigra are labeled. Using the same outcome measures encapsulated GDNF-producing cells will be implanted strategically to attract appropriate outgrowth in another experiment. Some monkeys will be studied for three years to allow for more complete restoration, determine extent of recovery, and possible side effects, such as dyskinesia. Together, these experiments will measure the degree of functional recovery attained through the placement of DA-specific grafts, subject to proper regulatory influences, into more physiological sites. Results from these experiments will be compared with behavioral, morphological, and biochemical data generated from Projects 1 & 2, as well as with prior transplants done under similar conditions in St. Kitts green monkeys.

项目3。恢复神经功能的nigral靶向策略 尽管胚胎DA神经元的纹状体内移植物存活，但将神经突入宿主大脑，提高移植物附近的DA水平，并恢复经过帕金森MPTP MPTP治疗的猴子的运动功能，但人类的功能益处可变，有些有限，有时与失调有关。这些局限性可能是由于移植物在纹状体中的异位放置以及多巴胺的失调释放。最近的研究表明，将胚胎底根（SN）嫁接到 胚胎纹状体的宿主SN和移植物进入纹状体，可用于促进从含DA的神经突向适当靶标的定向纤维生长。实验拟议的基于这些知识。假设是，将胚胎纹状体的共捕获到纹状体和腹侧脑脑组织与底底nigra相邻的腹侧室内组织将改善恢复，因为替换nigral细胞可以在NIGRA中调节，并在正常靶区域提供适当的多巴胺释放。行为措施将 评估功能恢复，DA神经元的免疫组织化学标志物将用作目标区域移植物存活的指标，并将确定生化效应。共聚焦和电子显微镜将有助于描绘由共移植物引起的电路重建。在牺牲之前，将逆行示踪剂氟化物枯萎被注射到尾状或壳中，以确定NIGRA中的嫁接多巴胺能神经元是否被标记。在另一个实验中，使用相同的结果度量封装的gdnf生产细胞将被战略性地植入，以吸引适当的生长。将研究一些猴子三年，以进行更完整的修复，确定恢复程度以及可能的副作用，例如运动障碍。总之，这些实验将通过放置DA特异性移植物（受适当的调节影响）的位置来衡量实现的功能恢复程度，并将其放入更多的生理部位。这些实验的结果将与项目1和2产生的行为，形态和生化数据以及在圣基茨绿猴相似条件下进行的先前移植物进行比较。