Project 5 Modulation and Function of 5HT2C Receptors

项目5 5HT2C受体的调节和功能

基本信息

批准号：
8330304
负责人：
Ronald B. Emeson
金额：
$ 23.35万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8330304
关键词：
Ablation Addictive Behavior Address Adenosine Adult Affect Amino Acids Animal Model Antidepressive Agents Antipsychotic Agents Anxiety Back Behavior Behavior Disorders Behavioral Behavioral Paradigm Binding Brain Brain region Caring Cell physiology Cells Complement Coupling Development Diagnosis Discipline of Nursing Disease Dopamine Dysthymic Disorder Epigenetic Process Exhibits Feeding behaviors Generations Genetic Genetic Polymorphism Growth Human Hypothalamic structure Inosine Laboratories Maternal Behavior Mediating Mental Depression Mental disorders Messenger RNA Modification Molecular Mood Disorders Mothers Mouse Strains Mus Mutant Strains Mice Nervous system structure Neuraxis Neurons Patients Pattern Physiological Positioning Attribute Primer Extension Pro-Opiomelanocortin Process Property Protein Isoforms Proteins RNA RNA Editing Receptor Gene Recombinant Inbred Strain Regulation Research Resources Rewards Schizophrenia Seizures Serotonin Signal Transduction Sleep Specificity System Therapeutic Time Transcript base cognitive function design extracellular flexibility insight mRNA Expression mutant novel offspring protein expression pup receptor response serotonin receptor tool

项目摘要

The 2C-subtype of serotonin receptor (5HT2CR) has been implicated in a number of human psychiatric and behavioral disorders, including MOD, dysthymia, obsessive-compulsive disease, anxiety, and schizophrenia. Studies from the Emeson laboratory were the first to demonstrate that that the function of the 5HT2CR is modulated by a novel RNA modification process referred to as RNA editing. Editing of 5HT2CR transcripts is responsible for the cell-specific expression of as many as twenty-four 5HT2CR isoforms and is proposed to represent a regulatory mechanism by which cells modulate their response to extracellular signals by altering the efficacy and specificity of receptorG-protein interactions. More recent studies have demonstrated altera- tions in 5HT2cR editing in patients diagnosed with psychiatric disorders and in response to antidepressant and antipsychotic treatment. The long term objectives of the proposed research are to define the cellular mechanisms involved in the regulation of 5HT2CR signaling, the physiologic relevance of edited 5HT2CR iso- forms and possible relationships between 5HT2cR editing and affective disorders. In Project 5: Modulation and Function of 5-HT2c Receptors, Ron Emeson proposes three Aims to more fully elucidate the region- specific pattern of 5HT2cR editing in the developing nervous system, to examine genetic and epigenetic modulation of 5HT2CR editing patterns and to take advantage of genetically-modified mouse strains that sole- ly express a single, edited isoform of the 5HT2CR to examine the physiologic relevance of multiple 5HT2CR species in the CNS.In Aim I, Emeson will use pyrosequencing, primer-extension, and qRT-PCR-based strat- egies to define the region-specific repertoire of 5HT2cR mRNAs expressed in the brain from the onset of 5HT2CR expression through adulthood, changes in 5HT2pR editing in mouse strains with altered 5HT signal- ing (e.g.SERT polymorphisms, Pet-1knockout, recombinant inbred strains), as well as define the pattern of 5HT2CR editing in identified hypothalamic neurons in the basal state and in response to pharmacologic and physiologic perturbations. In Aim II, Emeson proposes to further develop mutant mouse strains solely ex- pressing the non-edited (INI) or fully-edited (VGV) isoforms of the 5HT2cR, since these isoforms demonstrate the greatest differences in receptorG-protein coupling efficacy. These studies will examine and characterize ":he pattern and level of expression of 5HT2CR mRNA and protein expression and assess the molecular basis of a decrease in 5HT2CR expression in INI-expressing mice that may represent an adaptive homeostatic mechanism. These studies will be extended to examine alterations in signaling for mutant mice using GTPy35S binding and changes in 5HT2CR-mediated responsiveness by assessing alterations in both pro-opi- omelanocortin expression and subsequent feeding behavior. In Aim III, Emeson will examine the phenotypic consequences resulting from sole expression of a single 5HT2CR isoform, focusing upon observed deficits in maternal care in INI-expressing mice, as well as mesolimbic dopamine-mediated reward behaviors that may underlie such behavioral alterations.

血清素受体 (5HT2CR) 的 2C 亚型与许多人类精神和疾病有关行为障碍，包括 MOD、心境恶劣、强迫症、焦虑症和精神分裂症。 Emeson 实验室的研究首次证明 5HT2CR 的功能是由称为 RNA 编辑的新型 RNA 修饰过程调节。 5HT2CR 转录本的编辑是负责多达 24 种 5HT2CR 同种型的细胞特异性表达，并被提议代表一种调节机制，细胞通过改变细胞来调节其对细胞外信号的反应受体G-蛋白相互作用的功效和特异性。最近的研究表明，诊断为精神疾病的患者中 5HT2cR 编辑以及对抗抑郁药物的反应和抗精神病治疗。拟议研究的长期目标是定义细胞参与 5HT2CR 信号传导调节的机制，编辑的 5HT2CR iso- 的生理相关性 5HT2cR 编辑与情感障碍之间的形式和可能的关系。项目5：调制和 5-HT2c 受体的功能，Ron Emeson 提出了三个目标来更全面地阐明该区域 - 发育中的神经系统中 5HT2cR 编辑的特定模式，以检查遗传和表观遗传调节 5HT2CR 编辑模式并利用转基因小鼠品系 ly 表达单一、编辑的 5HT2CR 亚型，以检查多个 5HT2CR 的生理相关性在目标 I 中，Emeson 将使用焦磷酸测序、引物延伸和基于 qRT-PCR 的策略例如定义从发病开始就在大脑中表达的 5HT2cR mRNA 的区域特异性库成年期的 5HT2CR 表达，5HT 信号改变的小鼠品系中 5HT2pR 编辑的变化 ing（例如SERT多态性、Pet-1敲除、重组近交系），以及定义 5HT2CR 编辑已识别的下丘脑神经元的基础状态以及对药理和药物的反应生理扰动。在《目标 II》中，艾默森建议进一步开发仅从前的突变小鼠品系。按下 5HT2cR 的非编辑 (INI) 或完全编辑 (VGV) 同工型，因为这些同工型表明受体G-蛋白偶联功效的最大差异。这些研究将检验并描述》：5HT2CR mRNA 和蛋白表达的模式和水平以及评估分子基础 INI 表达小鼠 5HT2CR 表达减少，这可能代表适应性稳态机制。这些研究将扩展到使用突变小鼠检查信号传导的变化通过评估 pro-opi- 的变化，GTPy35S 结合和 5HT2CR 介导的反应性变化黑皮素表达和随后的进食行为。在目标 III 中，艾默生将检查表型单一 5HT2CR 同工型的单独表达所导致的后果，重点关注观察到的缺陷表达 INI 的小鼠的母性护理，以及中脑边缘多巴胺介导的奖励行为可能是这种行为改变的基础。