Levodopa dyskinesia and striatal neuroplasticity

描述（由申请人提供）：帕金森病（PD）是一种由大脑化学物质多巴胺进行性丢失引起的大脑疾病。帕金森氏病患者用左旋多巴（左旋多巴）治疗，左旋多巴是多巴胺的前体。然而，L-DOPA疗法具有致残性副作用。大多数左旋多巴治疗的患者最终会受到运动波动和不正常的不自主运动的折磨，称为运动障碍。左旋多巴引起的运动障碍可能比帕金森病本身更致残。在严重的情况下，需要对基底神经节核如丘脑、苍白球或丘脑底核进行神经外科损伤以改善帕金森病并使左旋多巴剂量最小化。该建议是基于这样的假设，即左旋多巴治疗帕金森病和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。通过比较运动障碍和非运动障碍的基因表达模式，我们可以找到负责运动障碍的发展，或负责防止运动障碍的发展的关键因素。然后可以设计出特定的治疗方法，可以与左旋多巴共同使用，以预防运动障碍。我们建议调查的分子系统，改变左旋多巴诱导的运动障碍，并找到'分子签名'的运动障碍。我们将研究帕金森病死后壳核中的基因表达模式，以响应左旋多巴治疗（PD;具体目标1）和响应左旋多巴诱导的运动障碍（具体目标2），并将其与左旋多巴诱导的运动障碍大鼠模型（具体目标3）进行比较。然后将在大鼠模型中检查五个候选基因对运动障碍的发展或补偿的作用（具体目标4）。在基因阵列实验中，我们已经从运动障碍的大鼠模型中收集了数据，并从这些数据中收集了候选基因的列表。这些基因列表将与人类壳核中的发现进行交叉参考，以确定五种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，可以发现有趣的新的，意想不到的基因调控模式，并帮助制定新的假设。尸检样本为我们提供了直接接触人类状况的途径，而动物模型为我们提供了一个可以严格控制的实验系统，可以进行功能分析和假设检验。他们可以一起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.