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）和抑制蛋白协同作用以确保G蛋白偶联受体快速终止G蛋白介导的信号传导。通过纹状体多巴胺受体的多巴胺能信号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。多巴胺受体信号异常与帕金森病 (PD) 和多巴胺替代疗法引起的运动并发症（如左旋多巴引起的运动障碍）密切相关。多巴胺受体经历 GRK 和抑制蛋白依赖性脱敏，该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的基础。在多巴胺耗尽的纹状体中，慢病毒介导的GRK6过度表达使PD啮齿类和灵长类动物模型的行为和多巴胺受体信号转导正常化，这表明GRK在大脑多巴胺受体的调节中发挥着关键作用。该项目旨在探索GRK和视紫红质抑制蛋白在活体动物多巴胺能调节行为中的作用以及GRK体内功能的精细分子机制。 First Aim 将研究 GRK 亚型在拮抗 L-DOPA 诱导的偏侧帕金森病大鼠旋转和对 L-DOPA 的行为敏感性方面的具体作用。我们将编码野生型 GRK 同工型、选择性禁用不同功能的突变 GRK 或 GRK microRNA 的慢病毒注射到多巴胺耗尽的纹状体中，以敲低选择的同工型，并测试重复左旋多巴给药后的旋转行为。 Aim 2 旨在测试同时过表达抑制蛋白和 GRK 是否比单独过表达同一 GRK 更有效地抑制 L-DOPA 诱导的运动症状。在目标 3 中，我们将检查 GRK 表达或功能扰动引起的下游信号通路的变化。在目标 4 中，将研究利用受体脱敏过程来改善帕金森病治疗的可行性。这些实验的结果将有助于理清 GRK 和抑制蛋白亚型在体内调节大脑多巴胺能信号传导中的具体作用。这些研究将为开发新的治疗方法来控制帕金森病的运动缺陷和左旋多巴治疗的并发症铺平道路。公共健康相关性：帕金森病是一种神经退行性疾病，会导致运动问题，用左旋多巴治疗，左旋多巴是一种有效的药物，但随着时间的推移会失效，并且具有严重的副作用。我们不知道左旋多巴疗法出现问题的原因是什么，也不知道它是如何产生副作用的。该项目旨在探索抑制蛋白和 G 蛋白偶联受体激酶的蛋白质是否在左旋多巴治疗的并发症中发挥作用。