Levodopa dyskinesia and striatal neuroplasticity

左旋多巴运动障碍和纹状体神经可塑性

• 批准号: 6901092
• 负责人: CHRISTINE L KONRADI
• 金额: $ 29.15万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-07 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6901092
• 关键词: Parkinson' s disease; abnormal involuntary movement; brain disorder chemotherapy; clinical research; gene expression; human tissue; in situ hybridization; laboratory rat; levodopa; microarray technology; neural plasticity; polymerase chain reaction; postmortem; putamen; striated muscles; western blottings

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a brain disorder caused by progressive loss of the brain chemical dopamine. Patients with Parkinson's disease are treated with levodopa (L-DOPA), a precursor of dopamine. However, L-DOPA therapy has disabling side effects. Most patients on L-DOPA treatment are eventually afflicted with motor fluctuations and abnormal, involuntary movements known as dyskinesias. L-DOPA-induced dyskinesias can become more disabling than Parkinson's disease itself. In severe cases, neurosurgical lesioning of basal ganglia nuclei such as the thalamus, pallidum or subthalamic nucleus is needed to improve Parkinson's disease and to minimize L-DOPA dosage. The proposal is based on the hypothesis that L-DOPA treatment in Parkinson's disease, and L-DOPA-induced dyskinesia, are accompanied by unique patterns of gene expression in the putamen. By comparing the gene expression patterns of dyskinesia to non-dyskinesia, we may find the critical factors responsible for the development of dyskinesia, or responsible for preventing the development of dyskinesia. Specific therapies could then be devised that could be co-administered with L-DOPA to prevent dyskinesias. We propose to investigate the molecular systems that are altered in L-DOPA-induced dyskinesia, and to find the 'molecular signature' of dyskinesia. We will study gene expression patterns in the post mortem putamen in Parkinson's disease in response to L-DOPA treatment (PD; Specific Aim 1) and in response to L-DOPA-induced dyskinesia (Specific Aim 2), and compare it to a rat model of L-DOPA-induced dyskinesia (Specific Aim 3). The role of five candidate genes for the development of, or compensation for, dyskinesia will then be examined in the rat model (Specific Aim 4). In a gene array experiment we have already collected data from the rat model of dyskinesia and assembled lists of candidate genes from these data. The lists of genes will be cross-referenced with the findings in the human putamen to determine five most likely candidates to be tested in the rat model. Hypothesis testing will be combined with computer programs that can find interesting new, unanticipated patterns of gene regulation, and help to formulate new hypotheses. The post mortem samples provide us with direct access to the human condition, while the animal model provides us with an experimental system that can be tightly controlled and that permits functional analyses and hypothesis-testing. Together they can lead the way toward new treatments for dyskinesia.

描述（由申请人提供）：帕金森病（PD）是一种脑部疾病，由大脑化学物质多巴胺的逐渐丧失引起。帕金森氏症患者用多巴胺前体左旋多巴（L-DOPA）治疗。然而，左旋多巴治疗有致残的副作用。大多数接受左旋多巴治疗的患者最终都会出现运动波动和不正常的不自主运动，即运动障碍。左旋多巴引起的运动障碍可能比帕金森病本身更加致残。在严重的病例中，需要对基底神经节核（如丘脑、白球或丘脑下核）进行神经外科损伤，以改善帕金森病，并尽量减少左旋多巴的剂量。该建议是基于一种假设，即左旋多巴治疗帕金森病，以及左旋多巴诱导的运动障碍，伴随着壳核中独特的基因表达模式。通过比较运动障碍与非运动障碍的基因表达模式，我们可能会发现导致运动障碍发展的关键因素，或者负责预防运动障碍发展的关键因素。然后可以设计出与左旋多巴联合使用的特殊疗法来预防运动障碍。我们建议研究在左旋多巴诱导的运动障碍中发生改变的分子系统，并找到运动障碍的“分子特征”。我们将研究帕金森病死后壳核对左旋多巴治疗（PD; Specific Aim 1）和左旋多巴诱导的运动障碍（Specific Aim 2）的基因表达模式，并将其与左旋多巴诱导的运动障碍大鼠模型（Specific Aim 3）进行比较。五个候选基因在运动障碍的发展或补偿中的作用将在大鼠模型中进行检验（Specific Aim 4）。在基因阵列实验中，我们已经从运动障碍大鼠模型中收集了数据，并从这些数据中收集了候选基因列表。这些基因列表将与人类壳核的发现相互参照，以确定五个最有可能在大鼠模型中进行测试的候选基因。假设检验将与计算机程序相结合，这些程序可以发现有趣的、意想不到的基因调控模式，并有助于形成新的假设。尸体样本为我们提供了直接了解人类状况的途径，而动物模型为我们提供了一个可以严格控制的实验系统，并允许功能分析和假设测试。它们一起可以引领运动障碍的新疗法。