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Orphan Receptor Gprc5b in Retinoic Acid-induced Affective Behaviors

视黄酸诱导的情感行为中的孤儿受体 Gprc5b

基本信息

批准号：
10450922
负责人：
Cesare Orlandi
金额：
$ 15.4万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450922
关键词：
Acute Adult Affect Affective Amygdaloid structure Animal Model Anterior Antidepressive Agents Area Atherosclerosis Autopsy Behavior Biological Assay Biological Process Biology Bipolar Disorder Brain Brain region Cell physiology Cells Chronic Corn Oil Corpus striatum structure Corticotropin-Releasing Hormone Coupling Cues Data Development Diabetes Mellitus Diagnosis Disease Dopamine Dose Drug Targeting Drug or chemical Tissue Distribution Enterobacteria phage P1 Cre recombinase Ethanol Event Exhibits Family G-Protein-Coupled Receptors GPR12 gene GTP-Binding Proteins Gene Expression Genes Genetic Transcription Genome Goals Hippocampus (Brain)Human Human Genome In Situ Hybridization Inflammation Intraperitoneal Injections Knockout Mice Lead Ligand Binding Ligands Light Link Major Depressive Disorder Malignant Neoplasms Marble Mediating Melatonin Mental Depression Mental disorders Messenger RNA Mood Disorders Moods Mus Names Neuraxis Neurobiology Neuroglia Neurons Neurotransmitters Norepinephrine Orphan Parahippocampal Gyrus Pathologic Patients Peripheral Pharmacology Phylogenetic Analysis Physiological Play Population Prefrontal Cortex Process Property Proteins Regulation Research Resolution Retinoids Role Second Messenger Systems Series Serotonin Signal Transduction Structure Substantia nigra structure Sucrose Tail Suspension Temporal Lobe Testing Therapeutic Tretinoin Vitamin A adult neurogenesis anxiety-like behavior behavior test behavioral study biochemical tools brain cell cancer type cell type cingulate cortex conditional knockout dentate gyrus depressive behavior depressive symptoms experimental study fiber cell forced swim test gene interaction human disease human tissue in vivo kidney dysfunction member motor control motor learning mouse model nestin protein neurogenesis neuropsychiatry novel preference programs promoter protein function receptor receptor-mediated signaling response tool

项目摘要

Project Summary/Abstract The endogenous ligands activating ~100 G protein coupled receptors (GPCRs) are still unknown, hence they are named orphans. Considering their understudied biology and demonstrated essential physiological roles, orphan GPCRs represent important, unexploited pharmacological targets. A small family of four evolutionary conserved IDG-eligible orphan GPCRs, Gprc5(a-d), has been linked to the onset of a variety of human diseases, ranging from several cancer types, diabetes, inflammation, renal dysfunction and neuropsychiatric conditions. Nonetheless, Gprc5(a-d) control over intracellular signaling cascades and biological functions are poorly understood. Among them, Gprc5b is also the most expressed orphan GPCR in the central nervous system. Interestingly, members of this class of orphan GPCRs were originally described as retinoic acid- inducible GPCRs. Our working hypothesis is that retinoic acid regulates transcriptional programs in the adult brain by coordinating changes in expression levels of a set of genes that includes Gprc5b. These changes are brain region and cell-type dependent. Considering that Gprc5b expression is enriched in the dentate gyrus of the hippocampus, a region heavily targeted by retinoic acid, we believe that Gprc5b regulation could be prominent here. Furthermore, given that Gprc5b has conserved typical G protein coupling motifs, we hypothesize that changes in Gprc5b levels would alter cell signaling cascades and intracellular levels of second messengers that in turn will modulate cellular functions. A major role of the dentate gyrus consists in maintaining adult neurogenesis, a process that, according to available data, can be possibly regulated by both retinoic acid and Gprc5b. A deficit in adult neurogenesis is one of the main factors in the development of mood disorders. Remarkably, Gprc5b levels were found altered in patients with affective disorders, while retinoic acid has been shown to affect mood-related behaviors both in animal models and patients. Therefore, with this project we will test the hypothesis that, through the described chain of events, retinoic acid controls depressive- like behavior in mice by controlling Gprc5b levels in specific brain areas and cell subpopulations. To this end, we will first investigate the brain region and cell-type specific regulation of Gprc5b by retinoic acid administration in mice. In parallel, we will generate a Gprc5b brain conditional knockout by crossing Gprc5bflx/flx mice with mice expressing Cre recombinase under the control of nestin promoter (Nescre). This novel mouse model will be used to evaluate the role of Gprc5b in depressive-like and anxiety-like behaviors using a battery of tests including sucrose preference test, elevated plus maze, marble burying, tail suspension test, forced swim test, and open field. Similarly, we will test the hypothesis that Gprc5b mediates part of the retinoic acid effect on mood disorders by administering the same sequence of tests to retinoic-acid treated Gprc5bflx/flxNescre and control littermates. Overall, the proposed experiments will illuminate Gprc5b biology and lead to the development of much needed research tools to study the physiological role of this orphan GPCR in vivo.

项目总结/文摘