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Understanding the Role of COMT Variants in Sensorimotor Gating

了解 COMT 变体在感觉运动门控中的作用

基本信息

批准号：
7491398
负责人：
Victoria B Risbrough
金额：
$ 15.52万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-15 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7491398
关键词：
22q11 Deletion Syndrome 3-methoxytyramine Abbreviations Affect Alleles Animals Attention Attention Deficit Disorder Behavior Behavioral Binding Biological Models Bipolar Disorder Brain Catechol O-Methyltransferase Catecholamines Catechols Chromosomes Code Codon Nucleotides Cognitive Complementary DNA Complex Computer information processing Corpus striatum structure DNA Data Development Diagnosis Disease Dopamine Environmental Risk Factor Enzymes Epigenetic Process Exhibits Facility Construction Funding Category Future Gene Proteins Gene Targeting Generations Genes Genetic Genetic Polymorphism Genomics Hippocampus (Brain)Human Immune Ligation Link Localized Measures Mediating Membrane Mental Health Mental disorders Messenger RNA Metabolism Methionine Methyltransferase Methyltransferase Gene Missense Mutation Modeling Monoamine Oxidase Mus Mutagenesis Mutant Strains Mice Mutation NIH Program Announcements Nature Norepinephrine Obsessive-Compulsive Disorder Pathogenesis Pathway interactions Patients Performance Pharmacology Phenotype Physiology Play Polymerase Chain Reaction Prefrontal Cortex Process Protein Isoforms Regulation Reporting Research Risk Role Schizophrenia Series Short-Term Memory Signal Transduction Single Nucleotide Polymorphism Site Stress Symptoms Testing Tissues Upper arm Validation Valine Variant cognitive function disorder risk dopamine system dopamine transporter endophenotype homologous recombination interest mouse model neurochemistry neuropsychiatry neurotransmission novel phenylacetaldehyde prepulse inhibition response tool trait

项目摘要

DESCRIPTION (provided by applicant): A single nucleotide polymorphism (SNP), causing a missense mutation of codon 158 Valine to Methionine in the coding region (termed val158met), exists in the human catechol-o-methyltransferase (COMT) gene. This COMT-Met polymorphism is unique for humans and decreases COMT enzymatic activity 40% in prefrontal cortex tissue. This decrease in enzymatic activity can reduce dopamine clearance in the cortex and enhance dopamine signaling. Since evidence supports a reduction in dopamine signaling in prefrontal cortex in schizophrenia patients, the relationship between the COMT gene and schizophrenia has been extensively studied. Association studies of the COMT val158met SNP with schizophrenia risk are inconsistent, however, and support only a small contribution. Given the complexity and overlapping nature of most neuropsychiatric disorders, it is unlikely that a simple gene to complex trait mechanisms can be identified. Instead, it has been suggested that optimally reduced measures of neuropsychiatric function or "endophenotypes" may be more useful than diagnoses to understand genetic contributions to psychiatric disorders such as schizophrenia. Preliminary data indicate that prepulse inhibition is modulated by the COMT gene in both mice and humans. Prepulse inhibition is an operational measure of sensorimotor gating that is deficient in schizophrenia. Little is known about the functional mechanisms underlying COMT val158met effects on this and other schizophrenia endophenotypes. The COMT SNP is ideally suited for modeling in mice as it is a coding region SNP with a well characterized functional effect on the dopamine metabolism pathway, which is relatively conserved between humans and mice. Indeed, "expressing specific human alleles of interest in mice may help elucidate gene/protein regulation and function, providing novel model systems to study human genes related to brain development, physiology, pharmacology, neurochemistry, and behavior" (RFA NH08-050: Mouse Models Containing Human Alleles: Novel Tools to Study Brain Function). In response to this program announcement, two mutant mouse lines will be created, each carrying a human COMT gene with either the Valine or Methionine polymorphism. Studies will test the hypothesis that similar to humans, mice carrying the COMT-Val allele will show poor prepulse inhibition performance compared to mice carrying the COMT-Met allele. This mouse model of COMT val158met polymorphism could play a critical role in the identification of mechanisms of COMT effects on neuropsychiatric endophenotypes such as sensorimotor gating. In the future, this model can aid in examination of COMT gene vulnerability interactions with other genes or environmental factors relevant to schizophrenia and other neuropsychiatric disorders, such as stress, immune challenge, and developmental insult.

描述（由申请人提供）：人儿茶酚-O-甲基转移酶（COMT）基因中存在单核苷酸多态性（SNP），导致编码区密码子158缬氨酸错义突变为蛋氨酸（称为val 158 met）。这种COMT-Met多态性对人类来说是独特的，并使前额叶皮层组织中的COMT酶活性降低40%。这种酶活性的降低可以降低皮质中的多巴胺清除率并增强多巴胺信号传导。由于有证据支持精神分裂症患者前额叶皮质多巴胺信号传导减少，因此COMT基因与精神分裂症之间的关系已得到广泛研究。然而，COMT val 158 met SNP与精神分裂症风险的关联研究并不一致，并且仅支持很小的贡献。鉴于大多数神经精神疾病的复杂性和重叠性，不太可能确定一个简单的基因复杂的特质机制。相反，有人建议，最佳减少措施的神经精神功能或“内表型”可能比诊断更有用，以了解遗传贡献的精神疾病，如精神分裂症。初步的数据表明，前脉冲抑制调制的COMT基因在小鼠和人类。前脉冲抑制是一种感觉运动门控的操作措施，在精神分裂症中缺乏。关于COMT val 158 met对这种和其他精神分裂症内表型的作用的功能机制知之甚少。COMT SNP非常适合在小鼠中建模，因为它是一种编码区SNP，对多巴胺代谢途径具有充分表征的功能作用，这在人和小鼠之间相对保守。事实上，“在小鼠中表达特定的人类感兴趣的等位基因可能有助于阐明基因/蛋白质的调节和功能，提供新的模型系统来研究与大脑发育、生理学、药理学、神经化学和行为相关的人类基因”（RFA NH 08 -050：含有人类等位基因的小鼠模型：研究大脑功能的新工具）。为了响应这一计划的宣布，将创建两个突变小鼠品系，每个品系都携带具有缬氨酸或蛋氨酸多态性的人类COMT基因。研究将检验这样的假设，即与人类相似，携带COMT-Val等位基因的小鼠与携带COMT-Met等位基因的小鼠相比将显示出较差的前脉冲抑制性能。这种COMT val 158 met多态性的小鼠模型可以在鉴定COMT对神经精神内表型的作用机制（如感觉运动门控）中发挥关键作用。在未来，该模型可以帮助检查COMT基因的脆弱性与其他基因的相互作用或与精神分裂症和其他神经精神疾病相关的环境因素，如压力，免疫挑战和发育损伤。