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.恢复神经功能的黑质靶向策略 虽然纹状体内移植胚胎DA神经元存活下来，将神经突起送入宿主大脑，提高移植物附近的DA水平，并恢复帕金森病患者MPTP治疗的猴子的运动功能，但在人类中的功能益处一直是可变的，有些有限，有时还与运动障碍有关。这些局限性可能是由于移植物在纹状体的异位放置以及由此导致的多巴胺的异常释放所致。最近的研究表明，将胚胎黑质(SN)移植到 宿主SN和胚胎纹状体移植到纹状体中，可用于促进含DA的神经突起向适当的靶点定向生长。提出的实验建立在这一知识的基础上。假说是，将胚胎纹状体联合移植到纹状体和黑质附近的腹侧中脑组织将促进恢复，因为替代黑质细胞可以在黑质中调节，并在正常靶区提供适当的多巴胺释放。行为衡量标准将 评估功能恢复，DA神经元的免疫组织化学标记物将被用作移植物在靶区存活的指标，并将确定生化效应。共聚焦显微镜和电子显微镜将有助于描述联合移植可能导致的电路重建。处死前，将逆行示踪剂荧光金注射到尾状核或壳核，以确定黑质中移植的多巴胺能神经元是否被标记。在另一项实验中，使用相同的结果指标，包裹的产生GDNF的细胞将被战略性地植入，以吸引适当的生长。将对一些猴子进行为期三年的研究，以实现更完整的恢复，确定恢复的程度，以及可能的副作用，如运动障碍。总而言之，这些实验将测量通过将特定于DA的移植物置于更多的生理部位而获得的功能恢复的程度，这些移植物受到适当的调节影响。这些实验的结果将与项目1和2产生的行为、形态和生化数据进行比较，以及与之前在类似条件下对圣基茨绿色猴子进行的移植进行比较。