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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：
9127180
负责人：
Brian Y Chow
金额：
$ 19.2万
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/9127180
关键词：
Accounting Animals Biological Assay 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 Health 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 reconstitution response small molecule success targeted treatment technology development therapeutic biomarker 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.

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Optogenetic Control of Calcium Oscillation Waveform Defines NFAT as an Integrator of Calcium Load.

DOI：
10.1016/j.cels.2016.03.010
发表时间：
2016-04-27
期刊：
Cell systems
影响因子：
9.3
作者：
Hannanta-Anan P;Chow BY
通讯作者：
Chow BY

Rational Construction of Compact de Novo-Designed Biliverdin-Binding Proteins.

紧凑的从头设计的胆绿素结合蛋白的合理构建。

DOI：
10.1021/acs.biochem.8b01076
发表时间：
2018
期刊：
Biochemistry
影响因子：
2.9
作者：
Sheehan,MollyM;Magaraci,MichaelS;Kuznetsov,IvanA;Mancini,JoshuaA;Kodali,Goutham;Moser,ChristopherC;Dutton,PLeslie;Chow,BrianY
通讯作者：
Chow,BrianY

Optogenetic Rac1 engineered from membrane lipid-binding RGS-LOV for inducible lamellipodia formation