Project 5 Modulation and Function of 5HT2C Receptors

项目5 5HT2C受体的调节和功能

• 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
• 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

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2c亚型（5HT2CR）与许多人类精神疾病有关