Signaling regulation in the striatum in Parkinson's disease

帕金森病纹状体的信号调节

• 批准号: 8071044
• 负责人: Eugenia V Gurevich
• 金额: $ 33.41万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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/8071044
• 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; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Parkinson's disease is a neurodegenerative disorder that causes movement problems treated with levodopa, which is an effective drug but looses effectiveness in time and has severe side effects. We do not know what causes problems with levodopa therapy or how its produces its side effects. This project is designed to explore whether the proteins called arrestins and G protein-coupled receptor kinases play a role in complications of the levodopa therapy.

描述（由申请人提供）：G蛋白偶联受体激酶（GRK）和逮捕蛋白会协同起作用，以确保G蛋白偶联受体对G蛋白介导的信号的快速终止。通过纹状体多巴胺受体通过纹状体的多巴胺能信号传导在控制正常和患病大脑中多种形式的行为方面起着关键作用。多巴胺受体的信号传导异常与帕金森氏病（PD）和多巴胺替代疗法引起的运动并发症（如L-DOPA诱导的运动障碍）有关。多巴胺受体会经历GRK和抑制蛋白依赖性脱敏，并且在此过程中的缺陷可能是由多巴胺丧失或PD中的多巴胺能药物引起的信号传导异常的基础。慢病毒介导的GRK6在多巴胺贫血的纹状体中的过表达使PD的啮齿动物和灵长类动物模型中的行为和多巴胺受体信号归一化，这表明GRK在调节大脑中多巴胺受体的调节中起着至关重要的作用。该项目旨在探讨活动物中GRK和逮捕蛋白在行为的多巴胺能调节中的作用，以及体内GRK功能的精细分子机制。第一个目的将检查GRK同工型在拮抗L-DOPA诱导的旋转和对Hemiparkinsonian大鼠L-DOPA的行为敏化中的特定作用。我们将注入编码野生型GRK同工型，具有不同功能的突变体GRK或GRK microRNA，以敲低选择的型同工型，并在重复的L-DOPA给药后测试旋转行为。目标2旨在测试在抑制L-DOPA诱导的运动症状时，同时对抑制蛋白和GRK的过度表达是否比单独的GRK过度表达更有效。在AIM 3中，我们将检查由GRK表达或功能中扰动引起的下游信号通路的变化。在AIM 4中，将检查利用受体脱敏过程改善帕金森氏病治疗的可行性。这些实验的结果将有助于分解GRK和阻止同工型在体内调节大脑中多巴胺能信号传导中的特定作用。这项研究将为开发新型治疗方法的发展铺平道路，以控制帕金森氏病和L-DOPA疗法并发症中的运动缺陷。公共卫生相关性：帕金森氏病是一种神经退行性疾病，会导致用左旋多巴治疗的运动问题，这是一种有效的药物，但失去了时间的有效性并具有严重的副作用。我们不知道是什么原因导致左旋多巴疗法或其副作用。该项目旨在探索称为抑制蛋白和G蛋白偶联受体激酶的蛋白质是否在左旋多巴疗法并发症中起作用。