Rhythmicity and Synchrony in the Basal Ganglia

描述(由申请人提供)：这是西北大学尤德尔帕金森氏病研究卓越中心的续签申请，现已进入第10个年头。在上一次获奖期间，这个高生产率的研究团队对帕金森氏症的潜在机制做出了基本的见解，导致了50多篇同行评议的出版物。我们的研究还推动了一项成功的伊拉地平II期临床试验。该计划在D.James Surmeier博士的指导下继续进行。有4个科学项目、1个翻译项目、一个行政核心和一个分子生物学核心围绕两个中心主题建立：1)帕金森病选择性神经元脆弱性的决定因素；2)导致该疾病核心运动症状的网络病理生理学的决定因素。项目1由Surmeier博士指导，建立在上一次赠款期间的开创性工作基础上，以探索桥脚核和尼古丁在调节黑质多巴胺能神经元氧化应激中的作用。项目2由Savio Chan博士指导，研究帕金森病苍白球神经元出现同步节律性爆发的机制，重点是一类投射到纹状体的新型神经元。由Mark Bevan博士指导的项目3探索了丘脑底核的皮质和苍白球传入在驱动帕金森病患者振荡行为中的作用。项目4由查尔斯·威尔逊博士指导，探索脑深部刺激对症状有益的潜在机制。项目5，由理查德·米勒博士指导，是一个翻译项目； 该项目将测试一种新型选择性Cav1.3 L型钙通道拮抗剂以及两种抗炎药的神经保护潜力；该项目还将测试针对含有GluN2D的谷氨酸受体的新型基因疗法在帕金森病模型中产生症状缓解的能力。这些项目利用先进的分子、光遗传学、药物基因组学、成像和电生理方法来实现其目标。行政核心将监督方案预算/分包合同安排、一年两次的会议、外部和内部咨询委员会、方案出版物的存档和分发、NIH年度方案续签申请的汇编和提交以及方案网页的维护。分子核心将为每个项目提供基因表达分析，为基因分型提供咨询和协助，并在设计和构建用于基因敲除的病毒载体方面提供协助，并在用于基因输送的病毒载体的设计和建造方面提供协助。成功实现我们的规划目标应该会使我们更接近于应对帕金森氏病研究界面临的两大挑战：开发疾病修改疗法和开发更好、更持久的对症疗法。

DESCRIPTION (provided by applicant): This is a renewal application for the Northwestern University Udall Center of Excellence in Parkinson's disease Research, now in its 10th year. In the last award period, this highly productive research team made fundamental insights into the mechanisms underlying Parkinson's disease, resulting in over 50 peer-reviewed publications. Our studies also motivated a successful Phase II clinical trial with isradipine. The program continues under the direction of Dr. D. James Surmeier. There are 4 scientific projects, 1 translational project, an administrative core and a molecular biology core built around 2 central themes: 1) the determinants of selective neuronal vulnerability in Parkinson's disease and 2) the determinants of the network pathophysiology responsible for the core motor symptoms of the disease. Project 1, directed by Dr. Surmeier, builds upon ground-breaking work in the last grant period to pursue the role of the pedunculopontine nucleus and nicotine in regulating oxidant stress in substantia nigra dopaminergic neurons. Project 2, directed by Dr. Savio Chan, pursues the mechanisms governing the emergence of synchronous rhythmic bursting in globus pallidus neurons in Parkinson's disease, focusing on a novel class of these neurons that project to the striatum. Project 3, directed by Dr. Mark Bevan, explores the role of cortical and pallidal input t the subthalamic nucleus in driving oscillatory behavior in Parkinson's disease. Project 4, directed by Dr. Charles Wilson, explores the mechanisms underlying the symptomatic benefit of deep brain stimulation. Project 5, directed by Dr. Richard Miller, is a translational project; this project will test the neuroprotective potential of a novel selective antagonist of Cav1.3 L-type Ca2+ channels, as well as two anti-inflammatory agents; this project will also test the ability of novel gene therapy targeting GluN2D-containing glutamate receptors to produce symptomatic relief in a Parkinson's disease model. These projects make use of advanced molecular, optogenetic, pharmacogenomics, imaging and electrophysiological approaches to achieve their aims. The administrative core will oversee the program budget/subcontract arrangements, biannual meetings, external and internal advisory committees, archiving and distribution of program publications, compilation and submission of annual NIH program renewal applications, and maintenance of a program web page. The molecular core will provide gene expression analysis for each of the projects, provide consultation and assistance for genotyping, and provide assistance in the design and construction of viral vectors for gene knockdown and to provide assistance in the design and construction of viral vectors for gene delivery. The successful attainment of our programmatic goals should bring us closer to meeting the two grand challenges facing the Parkinson's disease research community: to develop a disease-modifying therapy and to develop better, longer lasting symptomatic therapies.