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）：许多因素使遗传复杂的疾病变得复杂。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在人类和模式生物中识别多基因变异方面产生了很大的兴趣，并取得了一些成功。但我们不能忽视生理复杂性的重要性，即使是在与复杂的生物系统相互作用时可能造成严重破坏的单一变异。这一概念在某些领域得到了很好的理解-例如发育，变性-但对于某些功能表型，如中枢神经系统的兴奋性障碍，它是研究不足。癫痫在遗传学上是复杂的，但作为典型的大脑兴奋性障碍，它也是研究其他更不了解的功能性疾病的主要例子，如精神分裂症和其他精神疾病，这些疾病也可能具有兴奋性病理学。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，这些分子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脑功能。虽然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上至关重要。最近，在小鼠中发现了编码Brunol 4的基因中的严重亚形突变，Brunol 4是RNA结合蛋白Bruno/CUGBP/CELF家族中脑特异性、海马富集的成员。Brunol 4突变体具有复杂的癫痫发作障碍，具体取决于Brunol 4基因型和遗传背景，并且还可能具有行为表型。基因表达谱分析揭示了在突变体中下调的非特异性表达基因的富集，其中几个已经在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相似的作用，例如当敲除时，但Brunol 4突变小鼠的临床和遗传评估表明，同时导致复杂癫痫发作障碍的是几个基因的协调失调。该研究计划的当前目标是通过使用以突变和转基因小鼠研究为中心的各种方法，了解Brunol 4协调调节其靶转录物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，但超越了多基因遗传，以了解复杂的神经系统疾病的结构。