Manipulating Gene Expression in the Dyskinesias of Parkinson's Disease

描述（由申请人提供）：该项目涉及帕金森病多巴胺能治疗的最致残并发症之一，即称为运动障碍的不自主运动的发展。运动障碍的潜在机制仍然未知，我们缺乏具体有效的治疗方法来根除它们。在动物模型中的研究表明，慢性转录因子ΔFosB的纹状体水平在慢性左旋多巴治疗期间持续增加。因此，有人假设ΔFosB可能调节负责改变多巴胺能药物反应的基因。在这里，我们将测试在非人灵长类动物中ΔFosB蛋白表达的转基因操作的效果。该项目中采用的新方法可能会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，我们将评估使用病毒载体介导的基因递送在帕金森病猴纹状体中过表达ΔFosB后的行为和分子变化。第二个目标将使用电生理记录检查这些动物的基底神经节回路，并将其与运动障碍的发展相关联。第三个目标是通过下调大鼠和猴内源性基因的表达来证实ΔFosB的作用。 该项目采用跨学科的不同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性的最终评估，这一系列的翻译研究旨在建立ΔFosB在运动障碍发展中的机制作用。此外，这些研究将评估ΔFosB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 ΔFosB consistently increase during chronic levodopa treatment. Therefore, it has been hypothesized that ΔFosB may regulate the genes responsible for altered responses to dopaminergic drugs. Here, we will test the effects of the transgenic manipulation of ΔFosB 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 ΔFosB 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 ΔFosB 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 ΔFosB in the development of dyskinesias. Furthermore, these studies will assess the clinical application of ΔFosB gene silencing as a therapeutic strategy in complicated Parkinson's disease.