Levodopa dyskinesia and striatal neuroplasticity

描述(申请人提供)：帕金森氏病(PD)是一种大脑疾病，由大脑化学物质多巴胺的进行性丧失引起。帕金森氏症患者使用左旋多巴(L-多巴)治疗，左旋多巴是多巴胺的前体。然而，L-多巴疗法有致残的副作用。接受L多巴治疗的大多数患者最终都会出现运动波动和称为运动障碍的异常、不自主运动。L-多巴诱发的运动障碍比帕金森氏症本身更具致残性。严重者需手术切除丘脑、苍白球或丘脑底核等基底节核团，以改善帕金森病，减少L多巴的剂量。该建议是基于这样一个假设，即L-多巴治疗帕金森病和L-多巴诱导的运动障碍，伴随着壳核中独特的基因表达模式。通过比较运动障碍和非运动障碍的基因表达模式，我们可能找到导致运动障碍发展的关键因素，或者负责防止运动障碍发展的关键因素。然后，可以设计出与L多巴联合应用以预防运动障碍的特定疗法。我们建议研究L-多巴诱发的运动障碍中发生改变的分子系统，并寻找运动障碍的分子特征。我们将研究帕金森病死后壳核对L-多巴治疗(PD；特异性目标1)和L-多巴诱导的运动障碍(特异性目标2)的响应，并将其与L-多巴诱导的大鼠运动障碍模型(特异性目标3)进行比较。然后，将在大鼠模型中检验五个候选基因在运动障碍的发生或补偿中的作用(特定目标4)。在基因阵列实验中，我们已经收集了运动障碍大鼠模型的数据，并从这些数据中收集了候选基因的列表。这些基因清单将与人类壳核中的发现进行交叉参考，以确定最有可能在老鼠模型中进行测试的五个候选基因。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，并帮助形成新的假设。尸检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并允许进行功能分析和假设检验的实验系统。它们一起可以引领运动障碍的新疗法。

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.