Genetic Regulation of Complex Neurological Disease

复杂神经系统疾病的基因调控

• 批准号: 7558261
• 负责人: WAYNE N. FRANKEL
• 金额: $ 38.06万
• 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/7558261
• 关键词: Alleles; Alternative Splicing; Animal Model; Architecture; Behavioral; Binding; Brain; Brain Diseases; Cell Culture Techniques; Cell Line; Central Nervous System Diseases; Clinical; Complex; Consensus; Development; Disease; Elements; Epilepsy; Equilibrium; Family; Functional disorder; Gene Expression; 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; Molecular Genetics; Mus; Mutant Strains Mice; Mutation; Neurologic; Neurotransmitter Receptor; Pathology; Phenocopy; Phenotype; Physiological; Polygenic Traits; Process; Proteins; RNA; RNA-Binding Proteins; Regulation; Research; Role; Schizophrenia; Signal Transduction; Surveys; Synapses; System; Testing; Transcript; Transgenic Mice; Transgenic Organisms; Translating; Untranslated Regions; Variant; Vision; combinatorial; complex biological systems; gene interaction; genetic variant; genome sequencing; genome-wide; interest; mRNA Stability; member; molecular phenotype; mouse model; mutant; nervous system disorder; neuronal excitability; non-genetic; novel; overexpression; 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引起了人们对鉴定人类和模式生物中的多基因变异的兴趣，并取得了一些成功。但是，我们不能忽视生理复杂性的重要性，即使是单一的变异，当它们与复杂的生物系统相互作用时，也会造成严重破坏。这一概念在某些领域（如发育、退化）得到了很好的认可，但对于某些功能表型（如中枢神经系统的兴奋性障碍），它还没有得到充分的研究。癫痫病的基因确实很复杂，但作为典型的大脑兴奋性障碍，它也为研究其他更不为人所知的功能障碍提供了一个主要的例子，比如精神分裂症和其他精神疾病，这些疾病也可能有兴奋性病理。神经元的兴奋性主要由离子通道和转运体、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，以达到兴奋和抑制的平衡，从而实现适当的高水平脑功能。尽管编码这些分子的基因中的顺式变异可以导致特定的表型，但调节其表达的反式因子对于维持这种更高水平的平衡至关重要，甚至可能是协调的水平。最近在小鼠中发现了一个严重的半胚突变，在编码Brunol4的基因中，Brunol4是RNA结合蛋白Bruno/CUGBP/CELF家族的一种脑特异性、海马富集的成员。Brunol4突变体具有复杂的癫痫发作障碍，这取决于Brunol4基因型和遗传背景，也可能具有行为表型。基因表达谱揭示了突变体中海马表达基因的富集，这些基因在mRNA和蛋白质水平上被下调，其中一些已经被证实是这样的。虽然已知这些分子在突触功能中有近似作用，例如当被敲除时，但对Brunol4突变小鼠的临床和遗传评估表明，是几个基因同时协调失调导致了复杂的癫痫发作。本研究项目目前的目标是通过以突变小鼠和转基因小鼠为中心的多种研究方法，了解Brunol4在大脑中协调调节其靶转录物表达的方式。该系统为理解复杂神经系统疾病的结构提供了一种受多基因遗传影响但又超越多基因遗传的新模型。