Rhythmicity and Synchrony in the Basal Ganglia

基底神经节的节律性和同步性

基本信息

批准号：
8898236
负责人：
DALTON JAMES SURMEIER
金额：
$ 133.98万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898236
关键词：
Achievement Advisory Committees Age Anti-Inflammatory Agents Anti-inflammatory Archives Automobile Driving Autonomic Dysfunction Award Basal Ganglia Behavior Bradykinesia Budgets Calcium Cell Nucleus Cerebral cortex Clinical Clinical Trials Communities Consultations Corpus striatum structure Deep Brain Stimulation Disease Disease Progression Disease model Dopamine Agonists Dyskinetic syndrome Economic Burden Education and Outreach Emotional FDA approved Functional disorder Gait Gene Delivery Gene Expression Profiling Genes Genotype Globus Pallidus Glutamate Receptor Goals Grant Health Image Impaired cognition Impairment Individual Isradipine Lesion Levodopa Maintenance Modeling Molecular Molecular Biology Motor Neurodegenerative Disorders Neurons Nicotine Operative Surgical Procedures Output Parkinson Disease Pathway interactions Patients Pattern Peer Review Periodicity Pharmaceutical Preparations Pharmacogenomics Pharmacotherapy Phase II Clinical Trials Phenotype Physiological Population Prevalence Protocols documentation Publications Research Research Personnel Research Project Grants Rest Tremor Risk Risk Factors Role Signal Transduction Smoking Staging Structure of subthalamic nucleus Substantia nigra structure Symptoms Testing Texas Therapeutic Tobacco Training United States National Institutes of Health Universities Viral Vector Work cholinergic clinical practice design and construction disability dopaminergic neuron dosage drug discovery gene therapy glutamatergic signaling improved insight meetings motor disorder network dysfunction neuron loss non-motor symptom novel novel therapeutic intervention optogenetics outreach oxidant stress programs public health relevance symptom management tool translational neuroscience treatment strategy web page

项目摘要

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.

描述（由申请人提供）：这是西北大学Udall Udall卓越中心帕金森氏病研究中心的续签申请，该研究已于第10年。在最后一个奖项时期，这个高产的研究团队对帕金森氏病的基本机制有了基本的见解，从而产生了50多个经过同行评审的出版物。我们的研究还激发了ISRADIPINE成功的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个转化项目，一个行政核心和一个分子生物学核心核心构建的2个中心主题：1）帕金森氏病中选择性神经元脆弱性的决定因素； 2）网络病理生理学的决定因素负责该疾病的核心运动症状。由Surmeier博士指导的项目1建立在最后一个赠款期间的开创性工作，以追求Pedunculopontine Nucleus和Nicotine在调节Nigra多巴胺能神经元中氧化剂胁迫中的作用。由Savio Chan博士执导的项目2探讨了帕金森氏病中Globus Pallidus神经元中同步节奏爆发的机制，重点介绍了将这些新型神经元投射到纹状体上的新型神经元。由马克·贝文（Mark Bevan）博士指导的项目3探讨了丘脑下核在推动帕金森氏病振荡行为中的皮质和苍白球输入的作用。由查尔斯·威尔逊（Charles Wilson）博士执导的项目4探讨了深脑刺激的症状益处的基础机制。由理查德·米勒（Richard Miller）博士执导的项目5是一个翻译项目；这项目将测试CAV1.3 L型Ca2+通道的新型选择性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Glun2D的谷氨酸受体的新型基因疗法的能力，以在帕金森氏病模型中产生症状缓解。这些项目利用高级分子，光遗传学，药物基因组学，成像和电生理方法来实现其目标。行政核心将监督计划预算/分包合同安排，双年度会议，外部和内部咨询委员会，计划出版物的归档和分发，汇编和提交年度NIH计划续签申请以及维护程序网页。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援助，并为基因敲低的病毒载体设计和构建提供帮助，并为基因传递的病毒载体设计和构建提供帮助。成功实现我们的程序目标应该使我们更加接近帕金森氏病研究界面临的两个巨大挑战：开发改善疾病的疗法并发展更好，更持久的症状疗法。