Genetic Regulation of Complex Neurological Diseases

复杂神经系统疾病的基因调控

基本信息

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
项目类别：
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&apos 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

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. 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。基因组测序和物种内变异的进展引起了人们对识别人类和模式生物的多基因变异的浓厚兴趣，并取得了一些成功。但我们不能忽视生理复杂性的重要性。在复杂的生物系统中运行时，即使是孟德尔变异也会造成严重破坏。对于功能表型，例如中枢神经系统兴奋性障碍，这个概念尚未得到充分研究。可以肯定的是，癫痫在遗传上是复杂的，但作为典型的大脑兴奋性障碍，它也可以作为解决其他难以破解的功能障碍的主要例子，例如自闭症和精神分裂症，这些障碍也可能具有兴奋性。其核心是病理学。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，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。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在更高、协调的水平上维持这种平衡至关重要。我们之前鉴定并表征了 Celf4（以前称为 Brunol4）的低效基因型和无效基因型，编码 RNA 结合蛋白 BRUNO/CUGBP/CELF 家族的大脑特异性成员。 Celf4突变体具有复杂的癫痫症和其他神经表型，例如多动、轻度肥胖和异常的社交互动。最近，人类 CELF4 缺陷揭示了这些症状以及其他症状，例如智力障碍。在我们最初的资助期间，我们发现 CELF4 与非常高密度的 RNA 颗粒紧密相关，并且靶向兴奋性神经元中的大量 mRNA。许多靶标与突触功能有关，并且它们在突变小鼠的神经元内往往在各个方向上失调，但有增加远离细胞体的表达的趋势。这些发现与 CELF4 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 CELF4 通过增加钠通道 Nav1.6 的表达对内在神经元过度兴奋的影响，以及通过受损的稳态可塑性引起的全系统失调的证据。两者的结合可能是疾病全面爆发的原因。在接下来的五年中，我们将更详细地研究 CELF4 分子功能的几个关键方面，包括在 CELF 耗尽时对 CELF4 靶 mRNA 的命运进行更精确/更深入的研究，以及首先观察 CELF4 的蛋白质组成。含有核糖核蛋白颗粒。这些研究将使我们能够充实 CELF4 和相关蛋白在翻译沉默中的作用。与此同时，我们将通过检查突变细胞培养物、急性脑切片和神经元可塑性的整体动物模型来探讨 CELF4 是否在塑造细胞反应中具有协调作用。