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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/摘要激活~100 G蛋白偶联受体（GPCR）的内源性配体仍然未知，因此它们他们被称为孤儿。考虑到它们未被充分研究的生物学和已被证明的基本生理作用，孤儿GPCR代表重要的、未开发的药理学靶点。一个四口之家的进化保守的IDG-合格的孤儿GPCR，Gprc 5（a-d），已经与多种人类肿瘤的发病有关。疾病，范围从几种癌症类型、糖尿病、炎症、肾功能障碍和神经精神疾病条件尽管如此，Gprc 5（a-d）对细胞内信号级联和生物学功能的控制仍然存在。不太了解。其中，Gprc 5 b也是中枢神经系统中表达最多的孤儿GPCR 系统有趣的是，这类孤儿GPCR的成员最初被描述为视黄酸- 诱导型GPCR。我们的工作假设是，视黄酸调节转录程序在成人通过协调包括Gprc 5 b在内的一组基因表达水平的变化来控制大脑。这些变化是大脑区域和细胞类型依赖。考虑到Gprc 5 b表达在海马齿状回中富集，海马体，一个被视黄酸高度靶向的区域，我们相信Gprc 5 b的调节可能是突出在这里。此外，考虑到Gprc 5 b具有保守的典型G蛋白偶联基序，我们假设Gprc 5 b水平的变化会改变细胞信号级联和细胞内第二信使水平，而这些信使反过来又会调节细胞功能。齿状回的主要作用在于维持成人神经发生，根据现有数据，这一过程可能受到两者的调节维甲酸和Gprc 5 b。成人神经发生的缺陷是情绪发展的主要因素之一紊乱值得注意的是，在情感障碍患者中发现Gprc 5 b水平改变，而维甲酸已经显示出影响动物模型和患者的情绪相关行为。因此，有了这个项目我们将测试的假设，通过所描述的事件链，维甲酸控制抑郁症- 通过控制特定脑区和细胞亚群中的Gprc 5 b水平，使小鼠的行为相似。为此目的，我们将首先研究视黄酸给药对Gprc 5 b的脑区域和细胞类型特异性调节对小鼠同时，我们将通过将Gprc 5 bflx/flx小鼠与小鼠杂交来产生Gprc 5 b脑条件性敲除。在巢蛋白启动子（Nescre）的控制下表达Cre重组酶。这种新型的小鼠模型将是用于使用一系列测试评估Gprc 5 b在抑郁样和焦虑样行为中的作用包括蔗糖偏好试验、高架十字迷宫、埋弹珠试验、悬尾试验、强迫游泳试验，开放的领域。类似地，我们将检验Gprc 5 b介导部分视黄酸作用的假设。通过对维甲酸处理的Gprc 5 bflx/flxNescre进行相同序列的测试，对照同窝出生仔。总的来说，拟议的实验将阐明Gprc 5 b生物学，并导致开发急需的研究工具来研究这种孤儿GPCR在体内的生理作用。