Contribution of Cis-acting Regulatory Polymorphisms to Psychiatric Disorders

顺式作用调节多态性对精神疾病的贡献

• 批准号: 7942917
• 负责人: Beverly H Koller
• 金额: $ 50万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942917
• 关键词: 3' Flanking Region; Accounting; Address; Affect; Alleles; Architecture; Area; Autistic Disorder; Behavior; Behavior Disorders; Behavior monitoring; Behavioral; Behavioral Paradigm; Brain; Candidate Disease Gene; Cerebrum; Chromatin; Cis-Acting Sequence; Clinical; Code; Codon Nucleotides; DRD4 gene; Development; Diagnosis; Disease; Dopamine; Drug usage; Environmental Impact; Environmental Risk Factor; Epigenetic Process; Evaluation; Functional RNA; Gene Expression; Gene Structure; Generations; Genes; Genetic; Genetic Engineering; Genetic Polymorphism; Genetic Recombination; Genetic Transcription; Genome; Heritability; Homologous Gene; Human; Human Genetics; Individual; Inherited; Link; Measurable; Measures; Mental disorders; Messenger RNA; Metabolism; Methaqualone; Methods; Methylation; Missense Mutation; Modeling; Monitor; Mus; Mutation; Neurologic; Nonsense Mutation; Nucleic Acid Regulatory Sequences; Orthologous Gene; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Play; Population; Process; Psychiatric therapeutic procedure; Reeler Mouse; Risk; Role; Serotonin; Staging; Stress; Structure; Techniques; Testing; Tissues; Translational Research; Validation; Variant; defined contribution; disorder risk; dopamine transporter; embryonic stem cell; gene interaction; genetic risk factor; human DRD4 protein; monoamine; mouse development; mouse model; neuropsychiatry; novel strategies; promoter; protein structure; response; reuptake; serotonin transporter

DESCRIPTION (provided by the applicant): This application addresses the broad Challenge Area (15) Translational Science and specific Challenge Topic: 15-MH-104 Mouse models containing human genes implicated in mental disorders Differences in gene expression patterns between individuals are common, and it has been suggested that the polymorphisms responsible for these differences may account for the majority of human phenotypic variability. Gene expression is likely determined by the combined impact of environmental factors and inherited polymorphisms in regulatory regions of genes that modulate transcription or affect mRNA processing. Abundant polymorphisms in cis-acting sequences have been identified in genes implicated in psychiatric disorders. However, the elucidation of the contributions of these polymorphisms, both alone and when inherited in combination with polymorphisms at other loci, has been extremely difficult. The lack of progress in this area contrasts sharply with the progress that has been made in the evaluation of polymorphisms that alter protein structure. Mouse lines have been generated in which coding variants identified in patients have been introduced into the orthologous mouse gene using what are now standard genetic engineering techniques. These lines have provided important information regarding the functional importance of these polymorphisms. However, this method can rarely be used to study regulatory variants, as generally these polymorphisms are in regions that are less well conserved between mouse and human. In this application we propose a novel approach for evaluation of the functionality of polymorphisms in non-coding regions of genes believed to act in cis to regulate gene expression. We propose the generation of mouse lines in which the mouse ortholog of the human polymorphic gene is excised and then replaced with the syntenic human locus carrying either the disease associated or protective allele. The impact of the polymorphisms on gene expression during all stages of development, both during normal rearing and in response to imposed environmental stresses, can then be monitored. In addition, these lines will provide an opportunity to follow epigenetic changes at the human loci and to determine whether expression changes manifest as alterations in the behavior of the mouse. A large body of evidence indicates that both inherited and genetic components contribute to the risk for development of behavioral and psychological disorders. Numerous genetic studies have examined association between the development of these illnesses and the inheritance of alleles of genes in the serotonin and dopamine pathways. However, these studies are often inconclusive. This limits the ability of this information to be used in a clinical setting. In this application we propose a new method for validation of the function of variations in gene structure which are believed to confer risk for disease. Additionally, we propose methods for examination of the mechanism by which subtle differences in the primary structure of a gene can modify individuals' susceptibly for developing psychiatric and behavioral disorders. The mouse lines we propose to generate will help to define gene-gene interactions by allowing the study of multiple defined polymorphisms in mouse models related to these illnesses. This will help to define the risk conferred, not only by individual polymorphism but also the risk to the individual when multiple polymorphisms are inherited. We believe that these studies will, therefore, provide important information helpful in both the diagnosis and treatment of psychiatric illnesses.

描述（由申请人提供）：本申请解决了广泛的挑战领域（15）转化科学和特定挑战主题：15-MH-104鼠标模型，其中包含涉及精神疾病的人物基因表达模式的人类基因差异很普遍，并且已经表明，这些差异的多态性可能占人类现象的多数差异。基因表达可能取决于环境因素和遗传性多态性在调节转录或影响mRNA处理的基因调节区域的综合影响。在与精神疾病有关的基因中已经确定了顺式作用序列中的丰富多态性。然而，阐明这些多态性的贡献，无论是单独的还是与其他基因座的多态性遗传时，都非常困难。该领域的缺乏进展与评估改变蛋白质结构的多态性的进步形成鲜明对比。已经生成了小鼠线，其中使用了现在的标准基因工程技术，将在患者中鉴定出的编码变体被引入到直系同源的小鼠基因中。这些线条提供了有关这些多态性功能重要性的重要信息。但是，这种方法很少可用于研究调节变体，因为通常这些多态性在小鼠和人之间不太保守的区域中。在此应用中，我们提出了一种新的方法，用于评估被认为在CIS中作用以调节基因表达的基因的非编码区域的多态性功能。我们提出了小鼠系的生成，其中切除人多态基因的小鼠直系同源物，然后用携带疾病或保护性等位基因的同步人基因座取代。然后可以监测多态性在正常饲养和对施加的环境压力的响应期间的各个发育阶段的基因表达的影响。此外，这些线将提供一个机会，以遵循人类基因座的表观遗传变化，并确定表达变化是否表现为小鼠行为的改变。大量证据表明，遗传成分和遗传成分均导致行为和心理疾病的发展风险。大量遗传研究检查了这些疾病的发展与5-羟色胺和多巴胺途径中基因等位基因的遗传之间的关联。但是，这些研究通常尚无定论。这限制了该信息在临床环境中使用的能力。在此应用中，我们提出了一种验证基因结构变异功能的新方法，该方法据信赋予疾病风险。此外，我们提出了检查基因主要结构上微妙差异的机制方法，可以使个体的精神病和行为障碍对个体的敏感性进行修改。我们建议生成的小鼠线将通过研究与这些疾病有关的小鼠模型中的多种定义多态性来帮助定义基因 - 基因相互作用。这将有助于定义施加的风险，不仅是个人多态性的，而且在继承了多种多态性时对个人的风险。因此，我们认为这些研究将提供重要的信息，这有助于对精神病的诊断和治疗。