Expression and Function of the Alpha 7 Nicotinic Receptor in Schizophrenia

精神分裂症中α7烟碱受体的表达和功能

基本信息

批准号：
8398953
负责人：
SHERRY LEONARD
金额：
--
依托单位：
VA EASTERN COLORADO HEALTH CARE SYSTEM
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：
2011-01-01 至 2013-01-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8398953
关键词：
Affect Agonist Amino Acid Sequence Autopsy Binding Binding Sites Brain Bungarotoxins Candidate Disease Gene Cell Line Chimera organism Chromosomes, Human, Pair 3 Cigarette Smoker Cognition Cognitive deficits Complex Coupled Data Deletion Mutation Development Divalent Cations Dominant-Negative Mutation Drug Targeting Exons Gene Expression Gene Structure General Population Genes Genetic Transcription Genotype Hippocampus (Brain)Human Inflammation Length Ligand Binding Mammalian Cell Measures Messenger RNA Modeling Molecular Mono-S Neurons Nicotine Nicotine Dependence Nicotinic Receptors Nucleic Acid Regulatory Sequences Oocytes Patients Peptide Sequence Determination Peptides Play Prevalence Process Protein Subunits Proteins Receptor Gene Regulation Research Role Schizophrenia Self Medication Smoke Smoker Smoking Stream Stress Structure Surface Synapses System Transcription Initiation Site Translating Translations Veterans addiction alpha Bungarotoxin chimeric gene density drug development duplicate genes human tissue in vivo mRNA Expression mutant neurotransmitter release non-smoker promoter protein expression public health relevance receptor research study tissue culture

项目摘要

DESCRIPTION (provided by applicant): The 17 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is a replicated candidate gene for schizophrenia and is also protective in inflammation and stress. The protein subunit (17), derived from the gene, assembles with four other like subunits to form the pentameric, functional 17* receptor, which has five agonist-binding sites. The 17* receptor is an important target in drug development for cognitive deficits in schizophrenia. Agonist stimulation results in opening of the channel and entry of mono- and divalent cations, including Ca++, leading presynaptically to neurotransmitter release and postsynaptically to regulation at the post-synaptic density (PSD) and to down-stream changes in gene expression. Structure of CHRNA7, is complex; it is partially duplicated as a chimeric gene (CHRFAM7A). The chimera, CHRFAM7A, is expressed. Recent data suggests that CHRFAM7A acts as a dominant negative regulator of CHRNA7 binding and function. A 2bp deletion in CHRFAM7A is associated with schizophrenia and results in further decreasing CHRNA7 function. Schizophrenic patients have low levels of 17* receptors, as measured by binding of the ligand [125I]-1-bungarotoxin (I-BTX). Most of these patients are heavy cigarette smokers. The mRNA and protein in schizophrenic non-smokers is reduced compared to controls, but in the majority of subjects who smoke, there are normal levels of mRNA and protein. Thus, the low levels of I-BTX binding in schizophrenic patients are not explained by CHRNA7 mRNA or protein expression. We hypothesize that the duplicated gene, CHRFAM7A, acting as a dominant negative regulator, decreases the surface binding and function of 17* receptors. The current proposal will characterize the structure, expression and regulation of the CHRFAM7A gene and investigate its interaction with the full-length gene, CHRNA7.

描述（由申请人提供）： 17个神经元烟碱乙酰胆碱受体基因（CHRNA7）是精神分裂症的复制候选基因，在炎症和压力方面也具有保护性。源自该基因的蛋白质亚基（17）与其他四个类似亚基组装在一起，形成五型功能17*受体，该受体具有五个激动剂结合位点。 17*受体是精神分裂症认知缺陷的药物发展的重要目标。激动剂刺激导致在包括Ca ++在内的单阳离子和二价阳离子的进入，从而在突触前导致神经递质释放，并在突触后突触密度（PSD）和基因表达的下流变化下进行调节。 CHRNA7的结构是复杂的；它被部分复制为嵌合基因（CHRFAM7A）。嵌合体Chrfam7a表示。最近的数据表明，CHRFAM7A充当ChRNA7结合和功能的主要负调节剂。 CHRFAM7A中的2bp缺失与精神分裂症有关，并导致CHRNA7功能进一步降低。通过配体的结合[125i] -1-bungarotoxin（I-BTX），精神分裂症患者的17*受体水平较低。这些患者大多数都是吸烟者。与对照组相比，精神分裂症非吸烟者中的mRNA和蛋白质降低，但是在大多数吸烟的受试者中，mRNA和蛋白质水平正常。因此，精神分裂症患者的I-BTX结合水平较低，不会用CHRNA7 mRNA或蛋白质表达来解释。我们假设重复的基因CHRFAM7A充当主要的负调节剂，可降低17*受体的表面结合和功能。当前的建议将表征CHRFAM7A基因的结构，表达和调节，并研究其与全长基因CHRNA7的相互作用。