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：
9038736
负责人：
DALTON JAMES SURMEIER
金额：
$ 0.25万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9038736
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）：这是西北大学尤德尔帕金森病研究卓越中心的续展申请，现已进入第十个年头。在上一个奖项期间，这个高产的研究团队对帕金森病的潜在机制做出了根本性的见解，发表了 50 多篇经过同行评审的出版物。我们的研究还推动了伊拉地平 II 期临床试验的成功。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，围绕 2 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和 2）负责核心运动症状的网络病理生理学的决定因素的疾病。项目 1 由 Surmeier 博士领导，以上一个资助期的突破性工作为基础，研究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 博士领导，研究帕金森病患者苍白球神经元同步节律性爆发的机制，重点关注投射到纹状体的一类新型神经元。项目 3 由 Mark Bevan 博士领导，探索丘脑底核的皮质和苍白球输入在驱动帕金森病振荡行为中的作用。项目 4 由查尔斯·威尔逊 (Charles Wilson) 博士领导，探索深部脑刺激对症状有益的潜在机制。项目 5 由理查德·米勒 (Richard Miller) 博士指导，是一个转化项目；这该项目将测试一种新型选择性 Cav1.3 L 型 Ca2+ 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缓解症状的能力。这些项目利用先进的分子、光遗传学、药物基因组学、成像和电生理学方法来实现其目标。行政核心将监督项目预算/分包安排、半年一次的会议、外部和内部咨询委员会、项目出版物的归档和分发、年度 NIH 项目更新申请的汇编和提交以及项目网页的维护。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帮助，为基因敲低的病毒载体的设计和构建提供帮助，为基因递送的病毒载体的设计和构建提供帮助。成功实现我们的计划目标将使我们更接近于应对帕金森病研究界面临的两大挑战：开发疾病缓解疗法和开发更好、更持久的对症疗法。