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）：帕金森氏病（PD）是由脑化学多巴胺逐渐丧失引起的脑部疾病。帕金森氏病的患者接受了多巴胺前体的左旋多巴（L-DOPA）治疗。但是，L-DOPA疗法具有残疾的副作用。大多数接受L-DOPA治疗的患者最终都患有运动波动和异常的非自愿运动，称为运动障碍。与帕金森氏病本身相比，L-DOPA诱导的运动障碍可能变得更加残疾。在严重的情况下，需要对基底神经节核的神经外科病变，例如丘脑，苍白球或丘脑下核，以改善帕金森氏病并最大程度地减少L-DOPA剂量。该提案基于以下假设：帕金森氏病中的L-DOPA治疗以及L-DOPA诱导的运动障碍，并伴随着壳虫中基因表达的独特模式。通过将运动障碍的基因表达模式与非脱节障碍性进行比较，我们可能会发现负责发育障碍的关键因素，或者负责预防运动障碍的发展。然后可以设计特定的疗法可以与L-DOPA共同管理以预防运动障碍。我们建议研究在L-DOPA诱导的运动障碍中改变的分子系统，并找到运动性运动障碍的“分子特征”。我们将研究帕金森氏病后尸体甲状腺的基因表达模式，以应对L-DOPA治疗（PD；特定目标1），并响应L-DOPA诱导的运动障碍（特定的AIM 2），并将其与大鼠进行比较L-DOPA诱导的运动障碍的模型（特定目标3）。然后将在大鼠模型中检查五个候选基因在开发或补偿失调或补偿的作用（特定目标4）。在基因阵列实验中，我们已经从这些数据的大鼠模型中收集了大鼠模型的数据，并从这些数据中收集了候选基因列表。基因列表将与人壳中的发现交叉引用，以确定在大鼠模型中测试的五个最有可能的候选者。假设测试将与计算机程序结合使用，这些程序可以找到有趣的基因调节的新型，意外的模式，并有助于提出新的假设。验尸样本使我们可以直接访问人类状况，而动物模型为我们提供了一个可以严格控制的实验系统，并允许进行功能分析和假设测试。他们可以一起引导去运动障碍的新疗法。