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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.