Genetic Regulation of Complex Neurological Disease

复杂神经系统疾病的基因调控

• 批准号: 8015973
• 负责人: WAYNE N. FRANKEL
• 金额: $ 37.3万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015973
• 关键词: Alleles; Animal Model; Architecture; Behavioral; Brain; Brain Diseases; Central Nervous System Diseases; Clinical; Complex; Development; Disease; Epilepsy; Equilibrium; Family; Functional disorder; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Genotype; Goals; Hereditary Disease; Hippocampus (Brain); Human; Individual; Insertion Mutation; Intervention; Ion Channel; Knock-out; Lead; Membrane Potentials; Mental disorders; Messenger RNA; Modeling; Mus; Mutant Strains Mice; Mutation; Names; Neurotransmitter Receptor; Pathology; Phenotype; Physiological; Polygenic Traits; Principal Investigator; Proteins; RNA-Binding Proteins; Regulation; Research; Role; Schizophrenia; Signal Transduction; Synapses; System; Transcript; Transgenic Mice; Transgenic Organisms; Variant; Vision; combinatorial; complex biological systems; genetic variant; genome sequencing; interest; member; mutant; nervous system disorder; neuronal excitability; non-genetic; programs; success; synaptic function

DESCRIPTION (provided by applicant): Many factors make genetically complex diseases complex. Classically they are defined as an interaction between multiple genetic variants and non-genetic factors. Recent progress in genome sequencing and intraspecies variation has generated much interest in identifying polygenic variants in human and in model organisms, with some success. But one cannot lose sight of the importance of physiological complexity, even from single variants which can wreak havoc when they interact with a complex biological system. This concept is well appreciated in some arenas - e.g. development, degeneration - but for certain functional phenotypes such as excitability disorders of the central nervous system, it is understudied. Epilepsy is genetically complex to be sure, but as the canonical excitability disorder of the brain, it also serves as a leading example for approaching other, more poorly understood functional disorders such as schizophrenia and other psychiatric disorders which are likely to have excito-pathology as well. Neuronal excitability is determined primarily by molecules such as ion channels and transporters, neurotransmitter receptors, and synaptic proteins, which control membrane potential and synaptic signaling in order to achieve a balance of excitation and inhibition, thus enabling appropriate high-level brain function. Although cis-variants in genes encoding these molecules can lead to specific phenotypes, trans-factors that regulate their expression must be critical for maintaining this balance at a higher, perhaps even coordinated level. Recently a severely hypomorphic mutation was identified in mice, in the gene encoding Brunol4, a brain-specific, hippocampus-enriched member of the Bruno/CUGBP/CELF family of RNA binding proteins. Brunol4 mutants have a complex seizure disorder, depending upon Brunol4 genotype and genetic background, and may have behavioral phenotypes as well. Gene expression profiling revealed an enrichment of hippocampally-expressed genes that are downregulated in mutants, several of which have been validated as such at the mRNA and protein level. Although these molecules are known to have proximate roles in synaptic function, for example when knocked-out, clinical and genetic assessment of Brunol4 mutant mice suggests that it is the coordinate dysregulation of several genes simultaneously that leads to the complex seizure disorder. The current goal of this research program is to understand the way in which Brunol4 coordinately regulates the expression of its target transcripts in the brain, by using a variety of approaches centering on studies in mutant and transgenic mice. The system provides a new kind of model, influenced by, but extending beyond polygenic inheritance, for understanding the architecture of complex neurological disease.

描述（由申请人提供）：许多因素使遗传性复杂疾病变得复杂。传统上它们被定义为多种遗传变异和非遗传因素之间的相互作用。基因组测序和种内变异的最新进展引起了人们对识别人类和模式生物中的多基因变异的极大兴趣，并取得了一些成功。但人们不能忽视生理复杂性的重要性，即使是单一变异，当它们与复杂的生物系统相互作用时也会造成严重破坏。这个概念在某些领域很受欢迎 - 例如发育、退化——但对于某些功能表型，例如中枢神经系统的兴奋性障碍，它的研究还不够。癫痫在遗传上确实很复杂，但作为典型的大脑兴奋性障碍，它也可以作为解决其他人们知之甚少的功能性疾病的主要例子，例如精神分裂症和其他可能具有兴奋病理学的精神疾病。神经元兴奋性主要由离子通道和转运蛋白、神经递质受体和突触蛋白等分子决定，它们控制膜电位和突触信号传导，以实现兴奋和抑制的平衡，从而实现适当的高水平大脑功能。尽管编码这些分子的基因中的顺式变体可以导致特定的表型，但调节其表达的反式因子对于将这种平衡维持在更高甚至协调的水平必须至关重要。最近，在小鼠中发现了编码 Brunol4 的基因中的严重低效突变，Brunol4 是 RNA 结合蛋白 Bruno/CUGBP/CELF 家族中脑特异性、富含海马的成员。 Brunol4 突变体具有复杂的癫痫症，具体取决于 Brunol4 基因型和遗传背景，并且也可能具有行为表型。基因表达谱揭示了海马表达基因的富集，这些基因在突变体中下调，其中一些基因已在 mRNA 和蛋白质水平上得到验证。尽管已知这些分子在突触功能中具有直接作用，例如当被敲除时，Brunol4 突变小鼠的临床和遗传评估表明，几个基因同时协调失调导致了复杂的癫痫症。该研究项目当前的目标是通过以突变和转基因小鼠研究为中心的各种方法，了解 Brunol4 协调调节其目标转录本在大脑中表达的方式。该系统提供了一种新的模型，受多基因遗传的影响，但超出了多基因遗传的范围，用于理解复杂神经系统疾病的结构。