Optogenetic Toolbox for Studying Regulators of G-Protein Signaling in Addiction

用于研究成瘾中 G 蛋白信号传导调节因子的光遗传学工具箱

基本信息

批准号：
8989431
负责人：
Brian Y Chow
金额：
$ 19.33万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2015-08-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8989431
关键词：
Accounting Animals Biological Assay Biological Markers Boxing Brain region Catalytic Domain Cells Chimera organism Cocaine Communities Computer software Coupled Detection Dopamine Receptor Engineering Ensure Event Exhibits Feedback Future G Protein-Coupled Receptor Signaling GTP-Binding Protein Regulators GTP-Binding Protein alpha Subunits, Gs Glial Fibrillary Acidic Protein Guanosine Triphosphate Phosphohydrolases Heterodimerization Human Immunohistochemistry Individual Knock-out Laboratories Ligands Light Lighting Membrane Microscope Molecular Morphine Mus Nature Neurons Optics Pathway interactions Peptides Performance Pharmaceutical Preparations Phenotype Play Prefrontal Cortex Probability Protein Engineering Proteins RGS Proteins Reagent Regulation Reporter Role Safety Signal Transduction Time Toxic effect Transgenes Validation Virus addiction awake base cell type design drug of abuse in vivo inhibitor/antagonist knockout animal member mu opioid receptors nano neural circuit optogenetics public health relevance reconstitution response small molecule success technology development therapeutic target tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Regulators of G-protein signaling (RGS) are GTPase accelerating proteins (GAP) that fine-tune the timing and intensity of G-protein coupled receptor (GPCR) signaling through negative regulation. RGS proteins play important pathophysiological roles in addiction, with three RGS proteins in particular highly expressed in the mesolimbic pathway (RGS2, RGS4, and RGS9-2). These subtypes have been shown to influence the signaling of key mu-opioid and dopamine receptors, and vary in expression levels in response to drugs of abuse such as morphine and cocaine. The study of individual subtypes in vivo can be difficult due to compensatory activity that gives rise to subtle phenotypes in knockout animals, as well as the highly conserved nature of their catalytic domains that makes it pharmacologically challenging to create selective small molecule ligands. We propose to create new optogenetic tools that will enable the bi-directional activation and inhibition of individual RGS subtypes in a spatio-temporally precise and cell-type specific manner. This type of dynamic RGS subtype-specific control in vivo will bring a major methodological advance toward our basic understanding of RGS roles in addiction and their validation as therapeutic targets and biomarkers, by powerfully bridging the molecular level intracellular signaling events and cell type-level neural circuit dynamics that together mechanistically underlie downstream addictive phenotypes.

描述（由应用提供）：G蛋白信号传导（RGS）的调节剂是GTPase加速蛋白（GAP），通过负调节微调G蛋白偶联受体（GPCR）信号的时间和强度。 RGS蛋白在成瘾中起重要的病理生理作用，其中三种RGS蛋白质尤其在中唇途径中高度表达（RGS2，RGS4和RGS9-2）。这些亚型我们提出要影响关键的MU-Apoid和多巴胺受体的信号传导，并且在响应滥用药物（例如吗啡和可卡因）的响应中，表达水平有所不同。由于补偿活性导致敲除动物中的微妙表型以及其催化域的高度保守性，因此对体内各个亚型的研究可能很困难，这使其在药物上挑战以创建选择性的小分子配体。我们建议创建新的光遗传学工具，以实现双向激活和抑制单个RGS亚型以空间精确和细胞类型的特定方式。这种动态的RGS亚型特定于体内的控制将为我们对RGS在成瘾中的作用的基本理解以及它们作为治疗靶标和生物标志物的验证带来重大的方法论进步，并通过强大地桥接分子水平水平的细胞内信号事件和细胞类型的神经循环的动力学，这些动力学在机械上降低了其他层次底层的动态。