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：
8134927
负责人：
RON G. EMERSON
金额：
$ 23.58万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134927
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 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 Process Property Protein Isoforms Proteins RNA RNA Editing Recombinant Inbred Strain Regulation Research Resources Rewards Schizophrenia Seizures Serotonin Signal Transduction Sleep Specificity Therapeutic Time Transcript base cognitive function design extracellular flexibility insight 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.

5-羟色胺受体（5HT2CR）的2C囊型与许多人类精神科有关行为障碍，包括MOD，心律失常，强迫症，焦虑和精神分裂症。来自Emeson实验室的研究是第一个证明5HT2CR的功能是由新的RNA修饰过程调节，称为RNA编辑。 5HT2CR成绩单的编辑为负责多达24个5HT2CR同工型的细胞特异性表达，并提议代表一种调节机制，细胞通过改变细胞对细胞外信号的反应受体蛋白相互作用的功效和特异性。最近的研究表明 5HT2CR编辑的TICT在诊断患有精神疾病的患者中，并应对抗抑郁药和抗精神病药物。拟议研究的长期目标是定义细胞调节5HT2CR信号传导的机制，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。在项目5中：调制 5-HT2C受体的功能，罗恩·埃默森（Ron Emeson）提出了三个旨在更充分阐明该地区的目标在发育中的神经系统中的5HT2CR编辑的特定模式，以检查遗传和表观遗传 5HT2CR编辑模式的调节，并利用遗传改性的小鼠菌株 ly表达5HT2CR的单一编辑的同工型，以检查多个5HT2CR的生理相关性在CNS中的物种。定义从大脑中从大脑中表达的5HT2CR mRNA的特定区域特异性曲目。 5HT2CR在成年期间的表达，在5HT信号变化的小鼠菌株中的5HT2PR编辑变化 ING（例如，多态性，PET-1 Knockout，重组杂交菌株），并定义 5HT2CR在基础状态的下丘脑神经元中的编辑以及对药理和药理学和生理扰动。在AIM II中，Emeson提议进一步发展突变的小鼠菌株仅仅是按下5HT2CR的未编辑（INI）或完整编辑的（VGV）同工型，因为这些同工型证明了这些同工型受体蛋白偶联功效的最大差异。这些研究将检查和表征 ”：他的5HT2CR mRNA和蛋白质表达的表达方式和水平，并评估分子基础在表达的小鼠中5HT2CR表达的降低，这可能代表适应性稳态机制。这些研究将进行扩展，以检查使用使用 GTPY35的结合和5HT2CR介导的反应性的变化，通过评估两种反对的变化煎蛋素表达和随后的喂养行为。在AIM III中，Emeson将检查表型单个5HT2CR同工型的唯一表达产生的后果，重点是观察到的缺陷表达无性小鼠的孕产妇护理，以及可能可能这是这种行为改变的基础。