Novel Aspects of Golf Signaling

高尔夫信号的新颖之处

基本信息

批准号：
9029328
负责人：
JANET D ROBISHAW
金额：
$ 9.48万
依托单位：
GEISINGER CLINIC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2016-10-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029328
关键词：
Addictive Behavior Adenylate Cyclase Adverse effects Affect Aging Alzheimer&apos s Disease Automobile Driving Behavior Behavioral Binding Biochemical Biological Brain Brain region Clinical Complex Corpus striatum structure Data Defect Development Disease Dopamine Dopamine D1 Receptor Exhibits G-Protein Signaling Pathway GTP-Binding Proteins Gene Deletion Generic Drugs Genetic Goals Golf Government Grant Habits Health Heterotrimeric GTP-Binding Proteins Huntington Disease Injury Knock-in Mouse Knowledge Laboratories Lead Ligand Binding Locomotion Mediating Membrane Mental disorders Modeling Molecular Morphine Motivation Movement Disorders Mus Names Nature Neurologic Neurons Organism Output Parkinson Disease Pathway interactions Patients Pharmaceutical Preparations Phenotype Process Production Property Proteins Purinergic P1 Receptors Receptor Signaling Rewards Role Signal Pathway Signal Transduction Slice Specificity Structure Symptoms Synapses Testing Time To specify Work addiction base behavioral impairment cell type combat cost craving density design dimer interest learned behavior motor control mouse model nervous system disorder novel opioid abuse prescription opiate prevent promoter psychostimulant receptor response trafficking transmission process

项目摘要

DESCRIPTION (provided by applicant): G-protein signaling pathways control virtually every process in the body. At any time, the output of a particular neuron reflects the integration of several signaling pathways, while the neurological response of the organism requires the coordination of many more pathways operating in different brain regions, circuits and cell types. Our laboratory focused on how the diversity and specificity of these signaling pathways are encoded in the αβγ subunit structures of the G-proteins. Historically, the diverse α subtypes were assumed to specify their signaling roles. However, our work has challenged this dogma with the discovery of diverse γ subtypes whose unique signaling functions are identified for the first time. Notably, our production of Gng7-/- mice provides irrefutable proof that the γ7 subtype performs a novel role in the striatum by directing the ordered assembly of a specific G-αolfβ2γ7 heterotrimer that operates downstream of the D1 dopamine and A2a adenosine receptors in striatum. Forming the basis for this proposal, loss of the γ7 protein disrupts the G-αolfβ2γ7 assembly and produces defective morphine responsiveness. Because of the global nature of the gene deletion, it is not clear whether the defective morphine responsiveness reflects a requirement for the G-αolfβ2γ7 heterotrimer acting downstream of the D1 dopamine receptor (D1R) in striato-nigral neurons, the A2a adenosine receptor (A2aR) in striato-pallidal neurons, or both receptors. Accordingly, we will use our newly created conditional Gng7mice: 1) to genetically dissect the cell type specific roles of the G- G- αolfβ2γ7 heterotrimer in mediating spontaneous and acquired behaviors; 2) to identify the cellular basis and the affected signaling pathway(s); and 3) to explore to what extent the G-αolfβ2γ7 heterotrimer composition influences the ligand binding properties of these receptors. This new knowledge may eventually lead to the development of better strategies to prevent or ameliorate prescription opiate abuse that currently costs the US government $300 billion a year.

描述（由适用提供）：G蛋白信号通路几乎控制体内每个过程。在任何时候，特定神经元的输出反映了几种信号通路的整合，而组织的神经系统响应需要在不同大脑区域，电路和细胞类型中运行的更多途径进行协调。我们的实验室关注这些信号通路的多样性和特异性如何在G蛋白的αβγ亚基结构中编码。从历史上看，假定潜水员α亚型可以指定其信号传导作用。但是，我们的工作通过发现潜水员γ亚型的挑战，首次确定了独特的信号传导功能。值得注意的是，我们的GNG7 - / - 小鼠的产生提供了γ7亚型的无可辩驳的证据通过指导特定的G-αolfβ2γ7的有序组装来在纹状体中发挥新作用在纹状体中的D1多巴胺和A2A腺苷受体的下游操作的异三聚体。构成该提案的基础，γ7蛋白的损失破坏了G-αflβ2γ7的组装并产生有缺陷的吗啡反应性。 Because of the global nature of the gene deletion, it is not clear whether the defective morphine responsiveness reflects a requirement for the G-αolfβ2γ7 heterotrimer acting downstream of the D1 dopamine receptor (D1R) in striato-nigral neurons, the A2a adenosine receptor (A2aR) in striato-pallidal neurons, or both receptors.根据，我们将使用新创建的条件GNG7MICE：1）遗传剖析g-g-alphaolfβ2γ7异三聚体在中介中的细胞类型特异性作用赞助和获得的行为； 2）确定细胞基础和受影响的信号通路； 3）探索G-αflβ2γ7异三聚体组成在多大程度上影响这些受体的配体结合特性。这些新知识最终可能导致制定更好的战略，以预防或改善处方优化，以优化目前每年损失3000亿美元的滥用。