MODELS OF PARKINSONS DISEASE--THERAPEUTIC IMPLICATIONS

帕金森病模型——治疗意义

• 批准号: 2794332
• 负责人: MICHAEL D CRUTCHER
• 金额: $ 148.47万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2794332
• 关键词: Parkinson's disease; disease /disorder model

The proposed studies of this Center grant are focused on basic issues concerning the pathophysiology of Parkinson's disease (PD) and their therapeutic implications. These studies are, in part, concerned with animal models of PD and key aspects of the current basal ganglia- thalamocortical circuit models of parkinsonism. Project 1 is focused on the development of a more appropriate model of PD, in particular, one that exhibits the progressive nature of PD. The proposed model employs chronic systemic inhibition of complex I by rotenone in rodents with possible extension to primates. The conceptual connective framework for projects 2-5 is the exploration and testing of the current circuit model in both animal models and patients with PD. The studies in Project 2 explore in patients with PD the effects of deep brain stimulation (DBS) of the internal pallidum (GPi) and subthalamic nucleus (TN) on behavior and brain activation of 0-15 PET. These studies will help clarify functional correlates of the amelioration of specific parkinsonian symptoms by DBS of GPi and STN. Project 3 explores, in the primate metabolism in the thalamocortical circuit using a combination of single cell recording and FDG PET. Microdialysis combined with DBS of the STN will help to clarify the mode of action of DBS. This project will also examine the potential neuroprotective effects of STN inactivation. Project 4 explores key controversial issues regarding the pathophysiology of PD using microdialysis in primates. Metabotrophic glutamate receptors are abundant in STN and GPi and specific subtypes may be promising therapeutic targets. Project 5 will test the hypothesis that specific subtypes of metabotrophic glutamate receptors may play a therapeutically relevant role in PD. The Center will also provide state-of-the-art, multi-disciplinary training of fellows in research into parkinsonism and related conditions with an emphasis on translational.

该中心赠款的拟议研究集中在基本问题上 关于帕金森氏病（PD）的病理生理学及其 治疗意义。这些研究部分与 PD的动物模型和当前基底神经节的关键方面 - 帕金森氏症的丘脑皮层电路模型。项目1专注于 特别是PD模型的开发，特别是 表现出PD的渐进性。提出的模型采用慢性 可能会在啮齿动物中烤面包酮对复合物的全身抑制 扩展到灵长类动物。 项目2-5的概念连接框架是探索 在动物模型和 PD患者。项目2中的研究探讨了PD患者的 内部颗粒（GPI）和 丘脑下核（TN）关于0-15 PET的行为和脑激活。 这些研究将有助于阐明改善的功能相关性 GPI和STN的DBS的特定帕金森氏症状。项目3 探索使用丘脑皮质回路的灵长类动物代谢中 单细胞记录和FDG PET的组合。微透析合并 使用STN的DBS将有助于阐明DBS的作用方式。这 项目还将检查STN的潜在神经保护作用 失活。项目4探讨了有关的关键问题 PD的病理生理使用灵长类动物中的微透析。代谢性 谷氨酸受体在STN和GPI中很丰富，并且特定的亚型可能 成为有希望的治疗靶标。项目5将检验以下假设 代谢性谷氨酸受体的特定亚型可能会发挥作用 在PD中与治疗相关的作用。 该中心还将提供最先进的多学科培训 研究帕金森主义研究和相关条件的研究员的 强调翻译。