Genetic Regulation of Complex Neurological Diseases

复杂神经系统疾病的基因调控

• 批准号: 8679054
• 负责人: WAYNE N. FRANKEL
• 金额: $ 55.86万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679054
• 关键词: 3' Untranslated Regions; Accounting; Action Potentials; Acute; Animal Model; Attention; Autistic Disorder; Behavior; Binding; Brain; Brain Diseases; Brain region; Cell Culture Techniques; Cell Fractionation; Cell physiology; Central Nervous System Diseases; Clinical; Complex; Cues; Cytoplasmic Granules; Data; Disease; Dissection; Drosophila genus; Employee Strikes; Epilepsy; Epileptogenesis; Equilibrium; Etiology; Failure; Family; Focal Seizure; Foundations; Fractionation; Functional disorder; Funding; Future; Gene Expression Profile; Genes; Genetic; Genetic Translation; Genomics; Genotype; Hippocampus (Brain); Human; Hyperactive behavior; Individual; Intellectual functioning disability; Ion Channel; Kindling (Neurology); Lead; Learning; Membrane Potentials; Mental disorders; Messenger RNA; Metabolism; Mild obesity; Modeling; Molecular; Motor Seizures; Mus; Mutant Strains Mice; Mutation; Myopia; Nature; Neurologic; Neuronal Plasticity; Neurons; Neuropil; Neurotransmitter Receptor; Orthologous Gene; Pathology; Patients; Phenotype; Physiological; Polyribosomes; Process; Proteins; RNA; RNA-Binding Proteins; Regulation; Reporting; Ribonucleoproteins; Role; Schizophrenia; Seizures; Shapes; Signal Transduction; Slice; Social Interaction; Sodium Channel; Stimulus; Subcellular Fractions; Symptoms; Synapses; Synaptic plasticity; Syndrome; System; Therapeutic Intervention; Variant; Vision; autism spectrum disorder; complex biological systems; density; disability; disease phenotype; excitatory neuron; experience; genetic variant; genome sequencing; human disease; immunocytochemistry; interest; loss of function; member; mutant; nervous system disorder; neurobehavioral; neuron development; neuronal cell body; neuronal excitability; non-genetic; particle; research study; response; social; 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. Progress in genome sequencing and within-species variation has generated much interest in identifying polygenic variants from human and model organisms, with some success. But one cannot lose sight of the importance of physiological complexity; even Mendelian variants can wreak havoc when operating in a complex biological system. For functional phenotypes, such as excitability disorders of the CNS, this concept 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, harder-to-crack functional disorders, such as autism and schizophrenia, that are also likely to have excito- pathology at their cores. Neuronal excitability is determined primarily by molecules, such as ion channels and transporters, neurotransmitter receptors, and synaptic proteins, controlling membrane potential and synaptic signaling in order to achieve an appropriate balance of excitation and inhibition. 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, coordinated level. We previously identified and characterized hypomorphic and null genotypes in Celf4 (formerly known as Brunol4), encoding a brain-specific member of the BRUNO/CUGBP/CELF family of RNA binding proteins. Celf4 mutants have a complex seizure disorder and other neurological phenotypes, such as hyperactivity, mild obesity and abnormal social interaction. Very recently human CELF4 deficiency revealed these and additional symptoms such as intellectual disability. In our initial funding period, we found that CELF4 is most tightly associated with very high-density RNA granule particles and targets a vast number of mRNAs in excitatory neurons. Many targets are involved in synaptic functions, and they tend to be dysregulated within neurons of mutant mice - in all directions, but with a tendency towards increased expression away from the cell body. These findings are consistent with a role for CELF4 in control "translational silencing" at local, subcellular levels. We also obtained evidence for CELF4 effects on intrinsic neuronal hyperexcitation, via increased expression of sodium channel Nav1.6, and system- wide dysregulation via impaired homeostatic plasticity; the combination of the two presumably underlay full- blown disease. In the next five years we will examine in greater detail several key aspects of the molecular function of CELF4, including a greater precision/ depth examination of the fate of CELF4 target mRNAs when CELF is depleted and a first look at the protein composition of CELF4-containing ribonucleoprotein particles. These studies will allow us to flesh-out the role of CELF4 and related proteins in translational silencing. In parallel, we will explore whether CELF4 has a coordinating role in shaping cellular responses by examining mutant cell culture, acute brain slice and whole animal models of neuronal plasticity.

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。基因组测序和物种内变异的进展已经在识别来自人类和模式生物的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;即使是孟德尔变异体在复杂的生物系统中运行时也会造成严重破坏。对于功能表型，如中枢神经系统的兴奋性障碍，这一概念是研究不足。癫痫在遗传学上确实很复杂，但作为典型的大脑兴奋性障碍，它也是研究其他更难破解的功能性障碍的主要例子，如自闭症和精神分裂症，这些疾病也可能以兴奋病理学为核心。神经元兴奋性主要由分子决定，如离子通道和转运蛋白、神经递质受体和突触蛋白，控制膜电位和突触信号传导，以实现兴奋和抑制的适当平衡。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在更高的协调水平上维持这种平衡至关重要。我们以前确定和特征化的亚纯型和无效基因型Celf 4（以前称为Brunol 4），编码的RNA结合蛋白的BRUNO/CUGBP/CELF家族的脑特异性成员。Celf 4突变体具有复杂的癫痫发作障碍和其他神经学表型，如多动，轻度肥胖和异常的社会互动。最近，人类CELF 4缺乏症揭示了这些和其他症状，如智力残疾。在我们最初的资助期间，我们发现CELF 4与非常高密度的RNA颗粒颗粒最紧密相关，并靶向兴奋性神经元中的大量mRNA。许多靶点参与突触功能，它们往往在突变小鼠的神经元内失调-在所有方向上，但有远离细胞体表达增加的趋势。这些发现与CELF 4在局部亚细胞水平上控制“翻译沉默”的作用一致。我们还获得了CELF 4通过增加钠通道Nav1.6的表达对内在神经元过度兴奋的作用以及通过受损的稳态可塑性对系统范围的失调的作用的证据;这两种作用的结合可能导致疾病的全面爆发。在接下来的五年里，我们将更详细地研究CELF 4分子功能的几个关键方面，包括CELF耗尽时CELF 4靶mRNA的命运的更精确/深入的检查，以及首次研究含有CELF 4的核糖核蛋白颗粒的蛋白质组成。这些研究将使我们能够充实CELF 4和相关蛋白在翻译沉默中的作用。同时，我们将通过研究突变细胞培养、急性脑切片和神经元可塑性的整个动物模型来探索CELF 4是否在塑造细胞反应中具有协调作用。