The striatal cholinergic interneurons in Parkinson's disease and treatment

纹状体胆碱能中间神经元在帕金森病及其治疗中的作用

• 批准号: 9894969
• 负责人: Un Jung Kang
• 金额: $ 49.23万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894969
• 关键词: Ablation; Address; Affect; Age of Onset; Anatomy; Animals; Attenuated; Axon; Basal Ganglia; Chronic; Clinical; Clozapine; Complement; Complex; Corpus striatum structure; Coupled; Data; Deafferentation procedure; Deep Brain Stimulation; Development; Disease; Disease Progression; Dopamine; Dopaminergic Agents; Drug Exposure; Dyskinetic syndrome; Electrophysiology (science); Exposure to; Extracellular Signal Regulated Kinases; Financial compensation; Future; G-Protein-Coupled Receptors; Gene Expression; Gene Expression Profile; Genes; Genetic Recombination; Genetic Transcription; Hyperactive behavior; Hypersensitivity; Individual; Interneurons; Ion Channel; L-DOPA induced dyskinesia; Laboratories; Lesion; Levodopa; Ligands; Light; Literature; LoxP-flanked allele; Measures; Methods; Mitogen-Activated Protein Kinases; Molecular; Morphology; Motor; Mus; Muscarinic Acetylcholine Receptor; Neurites; Neurodegenerative Disorders; Neurons; Neurotransmitters; Outcome; Oxides; Parkinson Disease; Parkinsonian Disorders; Pharmacology; Pharmacotherapy; Phase; Physiological; Physiological Processes; Physiology; Preparation; Process; Property; Prophylactic treatment; Publications; Regulator Genes; Replacement Therapy; Reporting; Role; Severity of illness; Signal Transduction; Slice; System; Systems Biology; Testing; Therapeutic; Time; Transgenic Mice; Viral; abnormal involuntary movement; adenovirus mediated delivery; cell type; cholinergic; clinically relevant; designer receptors exclusively activated by designer drugs; experimental study; functional outcomes; in vivo; insight; interdisciplinary approach; mouse model; novel; novel therapeutics; prevent; receptor; response; targeted treatment; tool; transcriptome; transmission process

Project Summary/Abstract Dopaminergic therapy in Parkinson’s disease (PD) is the most successful example of rationale treatment approach addressing neurotransmitter deficit in neurodegenerative disorders. However, it is limited by motor fluctuations including dyskinesia that develops over several years of treatment. It is not clear if disease progression or treatment is the major factor in producing L-DOPA-induced dyskinesia (LID), but clinical and experimental evidences point to contributions of age of onset, disease severity, and chronic dopaminergic drug exposure. We have recently reported that elevated cholinergic signaling may be a major contributor to LID. Repeated L-DOPA administration in parkinsonian mice produces LID, which is associated with hyperexcitability of striatal cholinergic interneuron (ChI) evidenced by extracellular signal-regulated kinase (ERK) activation and enhanced response of ChI to dopamine. Moreover, the expression of LID was partially attenuated by preventing ERK activation or a muscarinic receptor antagonist. Ablation of ChI dramatically reduces LID in a mouse model of PD created by 6-OHDA lesion. To define the role of ChI further, we will utilize a novel method of selectively activating or suppressing ChI by Designer Receptor Exclusively Activated by Designer Drug (DREADD) system using transgenic mice expressing Cre in ChI and adenovirus-mediated delivery of floxed construct of DREADD to the striatal ChI. We will determine the role of ChI in LID development and expression separately. The outcome of this experiment would indicate fundamentally different approaches, either as a prophylaxis to prevent LID development or for symptomatic control of LID expression once it has already developed. We will then characterize cellular mechanisms of ChI hyperactivity associated with LID by examining gene expression changes, morphological alterations and electrophysiological properties. Multidisciplinary approaches will provide us necessary insights and tools to devise therapeutic approaches to LID.

项目摘要/摘要 帕金森氏病（PD）的多巴胺能疗法是理由治疗的最成功的例子 解决神经退行性疾病中神经递质缺陷的方法。但是，它受到限制 运动波动在内，包括运动障碍，在几年的治疗中发展。目前尚不清楚是否 疾病的进展或治疗是产生L-多巴引起的运动障碍（LID）的主要因素，但 临床和实验证据表明发病年龄，疾病严重程度和慢性病的贡献 多巴胺能药物暴露。我们最近报告说，胆碱能信号升高可能是 盖子的主要贡献者。帕金森尼亚小鼠重复的L-DOPA管理会产生盖子，这是 与细胞外的纹状体胆碱能中间神经元（CHI）的过度刺激性有关 信号调节激酶（ERK）激活和CHI对多巴胺的反应增强。而且， 通过防止ERK激活或毒蕈碱接收器，盖子的表达部分减弱 对手。 Chi的消融大大减少了由6-OHDA病变产生的PD的小鼠模型中的盖子。 为了进一步定义Chi的作用，我们将利用一种新颖的方法来选择性激活或抑制 设计器受体的CHI专门由设计器药物（Dreadd）系统使用转基因小鼠激活 在CHI和腺病毒介导的Dreadd构造向纹状体CHI的递送中表达CRE。 我们将分别确定CHI在盖子发育和表达中的作用。结果的结果 实验将表明从根本上不同的方法，要么作为预防 一旦盖子表达，请防止盖子发育或症状控制盖子 发达。然后，我们将表征与盖子相关的CHI多动症的细胞机制 检查基因表达变化，形态学改变和电生理特性。 多学科的方法将为我们提供设计治疗的必要见解和工具 盖子的方法。