Genetic Regulation of Complex Neurological Disease

复杂神经系统疾病的基因调控

基本信息

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
项目类别：
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

项目摘要

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复杂化。从经典上讲，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和模型生物中多基因变异的极大兴趣，并具有一定的成功。但是，即使是从单个变体中，当它们与复杂的生物系统相互作用时，也无法忽视生理复杂性的重要性。这个概念在某些领域很受欢迎 - 例如发育，变性 - 但对于某些功能表型，例如中枢神经系统的兴奋性障碍，它已被研究。可以肯定的是，癫痫在遗传上是复杂的，但是作为大脑的规范兴奋性障碍，它也是接近其他，更知名的功能性疾病（例如精神分裂症和其他精神疾病）的主要例子，这些功能障碍也可能具有兴奋性病理学。神经元兴奋性主要由分子（例如离子通道和转运蛋白，神经递质受体和突触蛋白）确定，它们控制膜电位和突触信号传导，以实现激发和抑制的平衡，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异可能会导致特定的表型，但是调节其表达的跨因素对于将这种平衡保持在更高甚至协调的水平上必须至关重要。最近，在编码Brunol4的基因中鉴定出了严重的低外形突变，Brunol4是RNA结合蛋白的Bruno/CUGBP/CELF家族的脑特异性，富含海马的成员。 Brunol4突变体具有复杂的癫痫发作，具体取决于Brunol4基因型和遗传背景，并且可能具有行为表型。基因表达谱分析表明，在突变体中下调的海马表达基因的富集，其中一些在mRNA和蛋白质水平上已被验证。尽管已知这些分子在突触功能中具有较近的作用，但例如，在敲除时，对Brunol4突变小鼠的临床和遗传评估表明，它同时导致了几个基因的坐标失调，导致复杂的癫痫发作障碍。该研究计划的当前目标是了解Brunol4通过使用以突变体和转基因小鼠研究为中心的各种方法来协调大脑中目标转录本在大脑中的表达的方式。该系统提供了一种新型的模型，该模型受到多基因遗传的影响，但延伸，以理解复杂的神经系统疾病的结构。