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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：本申请涉及广泛的挑战领域 (15) 转化科学和具体挑战主题：15-MH-104 含有与精神障碍有关的人类基因的小鼠模型个体之间基因表达模式的差异是常见的，并且有人认为，造成这些差异的多态性可能是人类表型变异的主要原因。基因表达可能是由环境因素和调节转录或影响 mRNA 加工的基因调控区域的遗传多态性的综合影响决定的。在与精神疾病有关的基因中已经鉴定出大量的顺式作用序列多态性。然而，阐明这些多态性的贡献，无论是单独的还是与其他位点的多态性结合遗传时，都是极其困难的。这一领域缺乏进展与改变蛋白质结构的多态性评估所取得的进展形成鲜明对比。已经产生了小鼠品系，其中使用现在标准的基因工程技术将在患者中鉴定的编码变体引入直系同源小鼠基因中。这些品系提供了有关这些多态性的功能重要性的重要信息。然而，这种方法很少可用于研究调控变异，因为通常这些多态性位于小鼠和人类之间保守性较差的区域。在本申请中，我们提出了一种新方法来评估基因非编码区多态性的功能，据信这些基因以顺式作用调节基因表达。我们建议产生小鼠系，其中人类多态性基因的小鼠直向同源物被切除，然后用携带疾病相关或保护性等位基因的同线人类基因座取代。然后可以监测多态性在所有发育阶段（无论是在正常饲养期间还是在响应施加的环境压力期间）对基因表达的影响。此外，这些细胞系还将提供一个机会来跟踪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，遗传和基因成分都会增加发生行为和心理障碍的风险。许多遗传学研究已经检验了这些疾病的发展与血清素和多巴胺途径中基因等位基因的遗传之间的关联。然而，这些研究往往没有结论。这限制了该信息在临床环境中使用的能力。在本申请中，我们提出了一种新方法来验证基因结构变异的功能，这些变异被认为会带来疾病风险。此外，我们提出了检查机制的方法，通过该机制，基因一级结构的细微差异可以改变个体对精神和行为障碍的易感性。我们建议生成的小鼠品系将通过允许研究与这些疾病相关的小鼠模型中的多个定义的多态性来帮助定义基因-基因相互作用。这将有助于定义不仅由个体多态性带来的风险，而且还有助于定义当多个多态性遗传时个体面临的风险。因此，我们相信这些研究将为精神疾病的诊断和治疗提供重要信息。