Nigrostriatal Tract Reconstruction

黑质纹状体束重建

• 批准号: 7764644
• 负责人: JOHN RICHARD SLADEK
• 金额: $ 19.91万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7764644
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Abbreviations; Accounting; Age; Animal Model; Animals; Award; Behavioral; Brain; Brain Stem; Calculi; Clinical Trials; Complex; Corpus striatum structure; Decision Making; Development; Distant; Dopamine; Dyskinetic syndrome; Elements; Embryo; Fiber; Future; Goals; Grant; Growth; Growth Factor; Human; Implant; Lateral; Lead; Location; Maintenance; Midbrain structure; Modeling; Motor; Movement Disorders; Neurites; Neurons; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pattern; Positioning Attribute; Primates; Program Research Project Grants; Protocols documentation; Rattus; Recovery of Function; Research; Rodent; Rodent Model; Signs and Symptoms; Site; Staging; Substantia nigra structure; Synapses; Testing; Tissues; Transplantation; Work; design; dopamine graft; dopaminergic neuron; graft function; improved; interest; neurite growth; neurochemistry; neurogenetics; nigrostriatal dopaminergic pathway; nigrostriatal pathway; nonhuman primate; novel; public health relevance; reconstruction; research study; response; restoration; stem; translational study

DESCRIPTION (provided by applicant): This exploratory project is designed to advance an unexpected finding that resulted from our program project grant on improving grant function in parkinsonian non-human primates. As part of the design we tested the ability of "helper" grafts to stimulate and guide the extension of neurites from grafts of ventral mesencephalon that contained dopaminergic neurons. We found that neurites from dopamine neurons could bridge the distance between the brain stem and the striatum and that they could extend from one distant helper graft to a second and ultimately to a third that was located in the striatum. This is an important finding with respect to the potential for reconstruction of elements of the nigrostriatal pathway because it places the grafted dopamine neurons in the mesencephalon where they have the opportunity to be contacted by appropriate afferent inputs. Graft therapy for Parkinsonism in both animal models and humans has utilized the striatum as the graft site for placement of dopaminergic neurons. While this convenient placement resulted in the release of dopamine directly into the region of the striatal target neurons, its shortcoming is that it places the donor neurons in a position that is removed from the normal pathway. In some clinical trials patients who initially showed some level of motor improvement eventually showed dyskinesias that are postulated to be due to uncontrolled or excessive release of dopamine by the grafts. The interesting thing about our finding is that we used striatal "helper" grafts to bridge the relatively long distance between the rostral mesencephalon and caudal striatum in the non-human primate and maintained the correct caudal to rostral position of the dissected pieces of the striatal anlagen. Thus, the dopamine neurites first reached the developing caudal portion of the striatum, and then somewhat remarkably continued to grow in a rostral direction to reach the second, later developing middle portion of the striatal donor graft. Ultimately, the fibers reached the third striatal "step" which was located in the host striatum. We hypothesize that a developmental gradient exists for the striatum from caudal to rostral that normally guides dopamine fibers that approach the striatum from the brain stem, and that a progressive wave of striatal growth factor activity exists to account for the continued extension of these fibers to reach the most distant sites within the striatum. Thus, we propose to test this in rodents prior to any further exploration in non-human primates. The program project grant is not going to be submitted for renewal which is a decision made by the executive committee of the P01 and if this exploratory proposal in rodent is awarded and proves successful then we will utilize this information to plan additional tests in the non-human primate of helper graft circuit reconstruction in behaviorally impaired animals as a possible future R01. PUBLIC HEALTH RELEVANCE: The proposed study has the potential to identify a key aid for successful circuit reconstruction of the dopaminergic pathway that is responsible for the manifestation of the signs and symptoms of Parkinson's disease. Our earlier studies in non-human primates provided a novel finding that can be tested more fully presently in a rodent model prior to moving forward with the more complex primate. We believe that more complete circuit reconstruction is crucial for optimizing graft function.

描述(由申请人提供)：这一探索性项目旨在推进我们的计划项目拨款在改善帕金森病非人类灵长类动物赠款功能方面的意外发现。作为设计的一部分，我们测试了“辅助”移植物刺激和引导含有多巴胺能神经元的腹侧中脑移植物的轴突延伸的能力。我们发现，来自多巴胺神经元的神经突起可以跨越脑干和纹状体之间的距离，它们可以从一个远处的辅助移植物延伸到第二个，最终延伸到位于纹状体的第三个辅助移植物。这是一个关于黑质纹状体通路元件重建潜力的重要发现，因为它将移植的多巴胺神经元放置在中脑，在那里它们有机会通过适当的传入输入联系到它们。在动物模型和人类中，帕金森综合症的移植治疗都利用纹状体作为放置多巴胺能神经元的移植部位。虽然这种方便的放置方式导致多巴胺直接释放到纹状体靶神经元区域，但它的缺点是将供体神经元置于一个从正常通路中移除的位置。在一些临床试验中，最初表现出一定程度运动改善的患者最终出现运动障碍，这被认为是由于移植物不受控制或过度释放多巴胺所致。我们的发现的有趣之处在于，我们使用纹状“助手”移植物在非人灵长类动物的吻侧中脑和尾侧纹状体之间架起了相对较长的距离，并保持了纹状体解剖段从尾端到嘴端的正确位置。因此，多巴胺神经突起首先到达纹状体发育中的尾侧部分，然后明显地继续沿吻部方向生长，到达第二个纹状体供体移植物的中段，后来又发育到中段。最终，纤维到达位于宿主纹状体的第三个纹状体“台阶”。我们假设，纹状体从尾侧到吻部存在一个发育梯度，通常引导多巴胺纤维从脑干接近纹状体，并且纹状体生长因子活性的递进波存在，以解释这些纤维继续延伸到纹状体内最远的位置。因此，我们建议在对非人类灵长类动物进行进一步研究之前，先在啮齿动物身上测试这一点。该计划项目拨款不会被提交续签，这是P01执行委员会做出的决定，如果在啮齿类动物中的这一探索性建议被授予并被证明成功，那么我们将利用这一信息来计划在非人类灵长类动物中进行更多的测试，以重建行为受损动物的辅助移植物回路，作为未来可能的R01。公共卫生相关性：这项拟议的研究有可能确定成功重建多巴胺能通路的关键辅助因素，该通路负责帕金森氏病的体征和症状的表现。我们早期对非人类灵长类动物的研究提供了一个新的发现，目前可以在啮齿动物模型中进行更全面的测试，然后再研究更复杂的灵长类动物。我们认为，更完整的电路重建是优化移植物功能的关键。