Manipulating Gene Expression in the Dyskinesias of Parkinson's Disease

操纵帕金森病运动障碍中的基因表达

• 批准号: 9305587
• 负责人: M. Maral Mouradian
• 金额: $ 4.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305587
• 关键词: Acute; Address; Alternative Therapies; Animal Model; Animals; Antiparkinson Agents; Area; Basal Ganglia; Behavior; Behavioral; Brain; Cells; Chronic; Corpus striatum structure; Data; Development; Discipline; Dopaminergic Agents; Dyskinetic syndrome; Evaluation; Exhibits; Frequencies; Gene Delivery; Gene Expression; Gene Silencing; Gene Transfer; Genes; Globus Pallidus; Goals; Health; Immunoblotting; Immunohistochemistry; Infusion procedures; Involuntary Movements; Lead; Levodopa; Link; Mediating; Modeling; Molecular; Monkeys; Motor; Names; Neurons; Outcome; Output; Parkinson Disease; Parkinsonian Disorders; Patients; Pharmacotherapy; Physiological; Play; Primates; Proteins; Protocols documentation; RNA Interference; Rattus; Recombinant adeno-associated virus (rAAV); Research; Rodent; Role; Small Interfering RNA; Solid; Structure of subthalamic nucleus; Technology; Testing; Therapeutic; Transgenic Organisms; Viral Vector; abnormal involuntary movement; clinical application; design; effective therapy; in vitro testing; knock-down; nonhuman primate; novel strategies; novel therapeutics; overexpression; protein expression; reduce symptoms; research study; response; tool; transcription factor; translational study

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.

描述（由申请人提供）：该项目解决了帕金森病多巴胺能治疗最严重的并发症之一，即称为运动障碍的不自主运动的发展。运动障碍的机制仍然未知，我们缺乏根除它们的具体和有效的治疗方法。动物模型研究表明，慢性转录因子 ΔFosB 的纹状体水平在长期左旋多巴治疗期间持续增加。 ΔFosB 可能调节对多巴胺能药物反应改变的基因。在此，我们将测试转基因操纵 ΔFosB 蛋白表达在非人类灵长类动物中的效果，该项目采用的新方法可能会解决病理生理学方面的问题并有助于开发新疗法。该项目包括三个具体目标，第一个目标是，我们将使用病毒载体介导的基因评估帕金森猴纹状体中 ΔFosB 过度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，并将其与运动障碍的发生联系起来，第三个目标是通过下调大鼠和猴子中内源基因的表达来确认 ΔFosB 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性的最终评估，这一系列的研究。转化研究旨在确定 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。

项目成果

Letter from the Editor-in-Chief: Growth of the Journal.

主编的来信：期刊的成长。

• DOI: 10.1007/s13311-019-00783-8
• 发表时间: 2019
• 期刊: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
• 作者: Mouradian,MMaral

Silica-coated magnetic-nanoparticle-induced cytotoxicity is reduced in microglia by glutathione and citrate identified using integrated omics.

• DOI: 10.1186/s12989-021-00433-y
• 发表时间: 2021-11-25
• 期刊: Particle and fibre toxicology
• 影响因子: 10
• 作者: Shin TH;Manavalan B;Lee DY;Basith S;Seo C;Paik MJ;Kim SW;Seo H;Lee JY;Kim JY;Kim AY;Chung JM;Baik EJ;Kang SH;Choi DK;Kang Y;Mouradian MM;Lee G
• 通讯作者: Lee G

Silica-coated magnetic nanoparticles impair proteasome activity and increase the formation of cytoplasmic inclusion bodies in vitro.

• DOI: 10.1038/srep29095
• 发表时间: 2016-07-05
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Phukan G;Shin TH;Shim JS;Paik MJ;Lee JK;Choi S;Kim YM;Kang SH;Kim HS;Kang Y;Lee SH;Mouradian MM;Lee G
• 通讯作者: Lee G