Manipulating Gene Expression in the Dyskinesias of Parkinson's Disease

描述（由申请人提供）：本项目解决帕金森病多巴胺能治疗中最致残的并发症之一，即称为运动障碍的不自主运动的发展。运动障碍的机制尚不清楚，我们缺乏具体有效的治疗方法来根除它们。动物模型研究表明，慢性左旋多巴治疗期间纹状体慢性转录因子（FosB）水平持续升高。因此，人们假设FosB可能调节了对多巴胺能药物反应改变的基因。在这里，我们将测试转基因操作（FosB）蛋白在非人灵长类动物中的表达效果。本项目采用的新方法可能解决病理生理方面的问题，并有助于开发新的治疗方法。该项目包括三个具体目标。在第一个目标中，我们将使用病毒载体介导的基因传递来评估帕金森猴纹状体中（FosB）过表达后的行为和分子变化。第二个目标是使用电生理记录检查这些动物的基底神经节回路，并将它们与运动障碍的发展联系起来。第三个目的是通过下调内源性基因在大鼠和猴子体内的表达来证实（FosB）的作用。该项目采用跨学科的多种实验方法来解决一个重要的健康问题。从病毒载体的构建，到体外测试，再到灵长类动物运动行为和生理相关因素的最终评估，这一系列的转化研究旨在确定（FosB）在运动障碍发展中的机制作用。此外，这些研究将评估（FosB）基因沉默作为复杂帕金森病治疗策略的临床应用。

DESCRIPTION (provided by applicant): This project addresses one of the most disabling complications of dopaminergic therapy in Parkinson's disease, namely the development of involuntary movements named dyskinesias. The mechanisms underlying dyskinesias remain unknown, and we lack specific and effective treatments to eradicate them. Studies in animal models have shown that the striatal levels of the chronic transcription factor (FosB consistently increase during chronic levodopa treatment. Therefore, it has been hypothesized that (FosB may regulate the genes responsible for altered responses to dopaminergic drugs. Here, we will test the effects of the transgenic manipulation of (FosB protein expression in non-human primates. The novel approach taken in this project may address pathophysiologic aspects and help develop new therapies. The project includes three specific aims. In the first aim, we will assess the behavioral and molecular changes following the overexpression of (FosB in the striatum of parkinsonian monkeys using a viral vector- mediated gene delivery. The second aim will examine the basal ganglia circuitry of these animals using electrophysiologic recordings and correlate them with the development of dyskinesias. And the third aim will confirm the role of (FosB by down-regulating the expression of the endogenous gene in rats and monkeys. This project employs diverse experimental approaches across disciplines to address an important health problem. From the construction of viral vectors, to the in vitro testing, to the final evaluations of motor behavior and physiologic correlates in primates, this sequence of translational studies is designed to establish the mechanistic role of (FosB in the development of dyskinesias. Furthermore, these studies will assess the clinical application of (FosB gene silencing as a therapeutic strategy in complicated Parkinson's disease. PUBLIC HEALTH RELEVANCE: One of the most disabling complications of dopaminergic therapy in Parkinson's disease is the development of involuntary movements named dyskinesias. The mechanisms underlying dyskinesias remain unknown, and we lack specific and effective treatments to eradicate them. This project is focused on the changes in gene expression within the brain that are associated with chronic drug therapy and lead to the development of dyskinesias. The goals of the project are to elucidate the mechanisms of dyskinesias and to test a novel therapy using gene silencing technologies in non-human primates.