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G-protein-, beta-arrestin- and ERK-signaling in alcohol use- and anxiety-disorders

酒精使用和焦虑障碍中的 G 蛋白、β-抑制蛋白和 ERK 信号传导

基本信息

批准号：
10240494
负责人：
JULIA ANN CHESTER
金额：
$ 33.79万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-10 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10240494
关键词：
Address Adverse effects Agonist Alcohol consumption Alcohol withdrawal syndrome Amygdaloid structure Anti-Anxiety Agents Anxiety Anxiety Disorders Arrestins Behavior Behavioral Assay Biological Assay Brain Brain region Cell model Corpus striatum structure Data Development Disease Dissection Dorsal Drug Addiction Drug Receptors Drug Targeting Drug usage Environment Enzymes Event Exhibits Extracellular Signal Regulated Kinases Fright Functional disorder Future G-Protein-Coupled Receptors GTP-Binding Proteins Goals Hippocampus (Brain)Individual Intake Knockout Mice Knowledge Light Link Malignant Neoplasms Measures Mediating Mental Depression Mitogen-Activated Protein Kinases Moods Mus Muscarinics Mutate Neurologic Opioid Opioid Receptor Opioid agonist Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacological Treatment Pharmacology Phosphorylation Phosphotransferases Physiological Play Post-Traumatic Stress Disorders Property Proteins Relapse Research Research Proposals Role Route Signal Pathway Signal Transduction Source Stress Structure Therapeutic addiction alcohol exposure alcohol use disorder anxiety-like behavior behavioral response beta-arrestin comorbidity delta opioid receptor designer receptors exclusively activated by designer drugs driving force drug development experimental study extracellular inhibitor/antagonist innovation insight interest kappa opioid receptors neuropsychiatric disorder novel precision medicine receptor reduced alcohol use scaffold tool withdrawal-induced anxiety

项目摘要

Project summary/Abstract G-protein coupled receptors (GPCRs) have long been a favorite target of pharmaceutical companies for treatment of myriad diseases as they are easily accessible and ubiquitously expressed. The predominant signal transduction routes for GPCRs are through the namesake G-protein pathway and by interaction with β-arrestin-linked scaffolds. Several research groups, including my own, have identified that G- proteins and β-arrestins can each uniquely modulate types of behavior. The discovery that drugs acting at GPCRs can exhibit so-called functional selectivity [i.e. activate only one pathway and not the other] has provided new opportunities for development of signaling biased drugs with fewer adverse effects. While G-proteins and β-arrestins mostly provide a divergence of signaling cascades, a small set of enzymes ambiguously play roles in both pathways. Of particular interest is the mitogen activated protein kinase `ERK' (extracellular signal-regulated kinase). ERK function and dysfunction has been linked to many diseases and disorders such as cancer, depression and drug addiction. Numerous studies have been conducted investigating how G-proteins and β-arrestins regulate ERK activity in simple cellular models. However, due to a lack of specific tools it has been much harder to establish how G-protein- mediated and β-arrestin-mediated ERK activation individually contribute to the modulation of behavior. Particularly it is of interest whether the total amount of ERK activation is the driving force behind the physiological effect, or whether the mechanism of activation (G-protein versus β-arrestin) is important. Recent pharmacological advances are now allowing us to propose experiments that will enable the dissection of G-protein and β-arrestin ERK activation in behavioral assays. For this proposal we will use G-protein and β-arrestin-biased drugs acting on delta opioid receptors as well as utilize innovative chemogenetic approaches to address our research questions. Our prior studies investigating delta opioid receptors have revealed that G-protein-biased drugs at this receptor can reduce alcohol use, whereas those delta opioids that activate ERK reduce anxiety. Upon completion of this study we will be able to address fundamental questions regarding signaling biased ERK activation related to alcohol use and anxiety-like behavior. More importantly, we will be able to describe `how biased' a delta opioid receptor drug must be and how /how much ERK it should be able to activate in order to efficaciously reduce alcohol use and anxiety, simultaneously. Such a drug would be very valuable given that alcohol use disorders are highly co-morbid with general anxiety disorders and post-traumatic stress disorders. Additionally, alcohol withdrawal induced anxiety is a major contributor to relapse and thus a bi-functional delta opioid drug would be a significantly better therapeutic option for patients suffering from alcohol use disorders than the currently available treatment options.

项目摘要/摘要 G蛋白偶联受体(GPCRs)长期以来一直是制药公司最喜欢的靶标治疗无数的疾病，因为它们很容易获得和无处不在的表达。占优势的 GPCRs的信号转导途径是通过同名的G蛋白途径和相互作用用β-arrestin连接的支架。几个研究小组，包括我自己的小组，已经确认G- 蛋白质和β阻滞素可以各自独特地调节行为类型。发现药物的作用 At GPCRs可以表现出所谓的功能选择性[即只激活一条途径，而不激活另一条途径] 为开发不良反应较少的信号偏向药物提供了新的机遇。虽然G蛋白和β抑制蛋白主要提供信号级联的分歧，但一小部分酶在这两种途径中都扮演着模棱两可的角色。特别令人感兴趣的是丝裂原激活蛋白。激酶‘ERK’(细胞外信号调节激酶)。ERK功能和功能障碍与许多疾病和障碍，如癌症、抑郁症和毒瘾。许多研究都有研究了G-蛋白和β-arrestins如何调节简单细胞内的ERK活性模特们。然而，由于缺乏具体的工具，很难确定G蛋白是如何- 介导的和β-arrestin介导的ERK激活分别对行为的调节起作用。尤其令人感兴趣的是ERK激活的总量是否是背后的驱动力生理效应，或激活机制(G-蛋白与β-arrestin)是否重要。最近的药理学进展现在使我们能够提出实验，使行为检测中G蛋白和β-arrestin ERK活性的分析。对于这个提案，我们将使用 G蛋白和β-arrestin偏向药物作用于增量阿片受体以及利用创新的解决我们的研究问题的化学遗传学方法。我们之前对Delta阿片类药物的研究受体显示，这种受体上的G蛋白偏向药物可以减少酒精的使用，而那些激活ERK的三角洲阿片类药物可以降低焦虑。在这项研究完成后，我们将能够解决与酒精使用有关的信号偏向ERK激活的基本问题焦虑样的行为。更重要的是，我们将能够描述“如何偏向”一个增量阿片受体药物必须是以及它应该能够激活多少ERK才能有效地减少酗酒和焦虑同时存在。鉴于酒精的使用，这种药物将是非常有价值的精神障碍与一般焦虑症和创伤后应激障碍高度并存。此外，酒精戒断引起的焦虑是复发的主要原因，因此是一种双功能对于酗酒患者来说，Delta阿片类药物将是一个明显更好的治疗选择与目前可用的治疗方案相比，这些疾病的发病率更高。