Signaling regulation in the striatum in Parkinson's disease

帕金森病纹状体的信号调节

基本信息

批准号：
8247113
负责人：
Eugenia V Gurevich
金额：
$ 33.44万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8247113
关键词：
ADRBK2 gene Acute Adverse effects Animal Model Animals Antiparkinson Agents Area Arrestins Behavior Behavioral Behavioral Model Beta-Adrenergic Receptor Kinase 2 Binding Brain Brain Diseases Corpus striatum structure Cultured Cells Data Development Disabled Persons Dopamine Dopamine Receptor Dopaminergic Agents Drug Addiction Dyskinetic syndrome Effectiveness Engineering Ensure Event Frequencies G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein-Coupled Receptors G-protein-coupled receptor kinase 3 GRK GRK6 gene GTP-Binding Proteins Goals Human Indium Individual Investigational Therapies L-DOPA induced dyskinesia Lesion Levodopa Life Light Mediating Mental disorders Methods MicroRNAs Modality Modeling Molecular Monkeys Motor Movement Mutagenesis Neurodegenerative Disorders Oxidopamine Parkinson Disease Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Plastics Play Primates Process Property Protein Isoforms Proteins Quality of life RGS Domain Rattus Receptor Signaling Regulation Relative (related person)Replacement Therapy Research Rodent Rodent Model Role Rotation Schizophrenia Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Sorting - Cell Movement Specificity Stream Subfamily lentivirinae Symptoms Technology Testing Therapeutic Time Translating base behavioral sensitization clinically relevant desensitization design dopaminergic neuron gene therapy improved in vivo motor deficit mutant nervous system disorder novel therapeutic intervention novel therapeutics overexpression protein complex receptor receptor sensitivity research study response tool trafficking

项目摘要

PROJECT SUMMARY G protein-coupled receptor kinases (GRK) and arrestins act in concert to ensure rapid termination of G protein- mediated signaling by G protein-coupled receptors. Dopaminergic signaling via striatal dopamine receptors play a critical role in controlling multiple forms of behavior in the normal and diseased brain. Abnormalities of signaling by dopamine receptors have been strongly implicated in Parkinson's disease (PD) and motor complications caused by dopamine replacement therapy such as L-DOPA-induced dyskinesia. Dopamine receptors undergo GRK- and arrestin-dependent desensitization, and deficits in this process may underlie signaling abnormalities caused by the loss of dopamine or by dopaminergic drugs in PD. The lentivirus- mediated overexpression of GRK6 in the dopamine-depleted striatum normalizes behavior and dopamine receptor signaling in the rodent and primate animal models of PD, suggesting a critical role for GRKs in the regulation of dopamine receptors in the brain. This project is designed to explore the role of GRKs and arrestins in the dopaminergic regulation of behavior in live animals as well as fine molecular mechanisms of the GRK function in vivo. First Aim will examine specific roles of GRK isoforms in antagonizing L-DOPA- induced rotations and behavioral sensitization to L-DOPA in hemiparkinsonian rats. We will inject lentiviruses encoding wild type GRK isoforms, mutant GRKs with different functions selectively disabled, or GRK microRNAs to knockdown select isoforms into the dopamine-depleted striatum and test for rotational behavior following repeated L-DOPA administration. The Aim 2 is designed to test whether simultaneous overexpression of an arrestin and a GRK is more potent than overexpression of the same GRK alone in suppressing L-DOPA-induced motor symptoms. In Aim 3, we will examine the alterations in down-stream signaling pathways caused by perturbations in the GRK expression or function. In Aim 4, the feasibility of harnessing the receptor desensitization process to improve therapy in Parkinson's disease will be examined. The results of these experiments will help to sort out specific roles of GRK and arrestin isoforms in regulating dopaminergic signaling in the brain in vivo. The studies will pave the way to development of novel therapeutic approaches to control motor deficits in Parkinsons' disease and complications of L-DOPA therapy.

项目概要 G 蛋白偶联受体激酶 (GRK) 和视紫红质抑制蛋白协同作用，确保快速终止 G 蛋白- G 蛋白偶联受体介导的信号传导。通过纹状体多巴胺受体的多巴胺能信号传导在控制正常和患病大脑的多种行为形式中发挥着关键作用。异常情况多巴胺受体信号传导与帕金森病 (PD) 和运动障碍密切相关多巴胺替代疗法引起的并发症，例如左旋多巴引起的运动障碍。多巴胺受体经历 GRK 和抑制蛋白依赖性脱敏，这一过程中的缺陷可能是 PD 中多巴胺缺失或多巴胺能药物引起的信号传导异常。慢病毒—— 多巴胺耗尽的纹状体中 GRK6 介导的过度表达使行为和多巴胺正常化受体信号转导在啮齿类和灵长类 PD 动物模型中的作用，表明 GRK 在 PD 中发挥着关键作用。大脑中多巴胺受体的调节。该项目旨在探索 GRK 的作用和视紫红质抑制蛋白在活体动物行为多巴胺能调节中的作用及其精细分子机制 GRK在体内的功能。 First Aim 将研究 GRK 同工型在拮抗 L-DOPA 中的具体作用诱导偏侧帕金森病大鼠的旋转和对左旋多巴的行为敏感性。我们将注射慢病毒编码野生型 GRK 同工型、选择性禁用不同功能的突变型 GRK，或 GRK microRNA 将选择的异构体敲低到多巴胺耗尽的纹状体中并测试旋转行为重复施用左旋多巴后。 Aim 2 旨在测试是否同时抑制蛋白和 GRK 的过表达比单独过表达相同的 GRK 更有效抑制左旋多巴引起的运动症状。在目标 3 中，我们将检查下游的变化 GRK 表达或功能扰动引起的信号通路。在目标 4 中，可行性将研究利用受体脱敏过程来改善帕金森病的治疗。这些实验的结果将有助于理清GRK和视紫红质抑制蛋白亚型在调节中的具体作用。体内大脑中的多巴胺能信号传导。这些研究将为开发新型治疗方法铺平道路控制帕金森病运动缺陷和左旋多巴治疗并发症的方法。