Identification of genetic pathways that regulate neuronal circuits in C. elegans

鉴定调节线虫神经元回路的遗传途径

基本信息

批准号：
8456849
负责人：
Salvatore James Cherra
金额：
$ 4.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8456849
关键词：
Affect Animals Behavior Behavioral Biological Models Brain Caenorhabditis elegans Calcium Candidate Disease Gene Cell Adhesion Molecules Cells Cholinergic Receptors Convulsions Data Development Disease Electron Microscopy Epidermis Epilepsy Equilibrium Fingers Frequencies Functional disorder Future Gene Mutation Genes Genetic Genetic Techniques Goals Homologous Gene Human Image Ion Channel Knock-in Mouse Knock-out Learning Light Locomotion Maps Mediating Memory Microscopy Molecular Morphology Mutate Mutation Nematoda Nerve Nervous system structure Neuroglia Neurons Pathway interactions Phenotype Physiological Population Process RNA Interference Regulation Rodent Model Schizophrenia Seizures Social Behavior Synapses Time Tissues Whole Organism autism spectrum disorder base cholinergic design effective therapy gain of function mutation loss of function loss of function mutation mutant nervous system disorder neural circuit neuroligin 1 neuropsychological new therapeutic target novel prevent receptor relating to nervous system synaptic function

Affect Animals Behavior Behavioral Biological Models Brain Caenorhabditis elegans Calcium Candidate Disease Gene Cell Adhesion Molecules Cells Cholinergic Receptors Convulsions Data Development Disease Electron Microscopy Epidermis Epilepsy Equilibrium Fingers Frequencies Functional disorder Future Gene Mutation Genes Genetic Genetic Techniques Goals Homologous Gene Human Image Ion Channel Knock-in Mouse Knock-out Learning Light Locomotion Maps Mediating Memory Microscopy Molecular Morphology Mutate Mutation Nematoda Nerve Nervous system structure Neuroglia Neurons Pathway interactions Phenotype Physiological Population Process RNA Interference Regulation Rodent Model Schizophrenia Seizures Social Behavior Synapses Time Tissues Whole Organism autism spectrum disorder base cholinergic design effective therapy gain of function mutation loss of function loss of function mutation mutant nervous system disorder neural circuit neuroligin 1 neuropsychological new therapeutic target novel prevent receptor relating to nervous system synaptic function

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项目摘要

DESCRIPTION (provided by applicant): Many neurological disorders are associated with genetic mutations that affect neuronal activity and synapse function. Understanding how these genes regulate normal circuit function will have profound impact on the management of such diseases. In addition to neurons, the brain contains nearly ten times as many non-neuronal glial cells, which support neuronal function and regulate excitation/inhibition balance. The studies of mammalian model systems are hindered by this cellular and genetic complexity of the mammalian brain. The use of a simple, whole organism model system has the advantages of reducing the cellular complexity, while maintaining the neuronal and non-neuronal connectivity under physiological conditions. The overall goal of this project is to uncover the mechanisms by which non-neuronal cells modulate neuronal excitation/inhibition balance. The roundworm, Caenorhabditis elegans, will be utilized as a model system for four main reasons: 1) its neuronal networks are formed and maintained through mechanisms that are conserved in humans, 2) it has a simple, fully mapped nervous system, 3) it is easy to manipulate through genetic techniques, and 4) it has well-conserved homologs to genes mutated in autism spectrum disorders and epilepsy. The goals of this study will be accomplished through the following specific aims: Aim 1: Identify genetic pathways in non-neuronal cells that regulate neuronal excitation/inhibition imbalance using an RNA- interference screen. Aim 2: Characterize the physical interactions between neurons and non-neuronal cells under excitation/inhibition imbalanced conditions utilizing a genetic approach to fluorescently tag cellular interactions. Aim 3: Determine whether modulation of non-neuronal cells can prevent excitation/inhibition imbalance caused by mutations in autism spectrum disorder genes. The completion of this application will provide a deeper understanding of the interactions between neurons and the surrounding non-neuronal cells under physiological and pathological conditions. Additionally, this study will uncover the pathogenic mechanism(s) of neurological disorders that affect synaptic functions, such as autism spectrum disorders or epilepsy. Finally, this project will provide potential targets for novel therapies for the treatment of autism spectrum disorders, epilepsy, and related neurological diseases. PUBLIC HEALTH RELEVANCE: Neural circuit activity imbalance underlies many forms of neurological disease, such as autism spectrum disorders, epilepsy, and schizophrenia, which affect nearly 3% of the population; however, there are no cures or long-term therapies. This project will uncover mechanisms that underlie neural circuit regulation, will shed further light onto our understanding of the disease process, and will provide new therapeutic targets for future treatments.

描述（由申请人提供）：许多神经系统疾病与影响神经元活动和突触功能的基因突变有关。了解这些基因如何调节正常电路功能将对此类疾病的管理产生深远的影响。除了神经元外，大脑还包含几乎许多非神经神经胶质细胞的十倍，这些细胞支持神经元功能并调节激发/抑制平衡。哺乳动物模型系统的研究受到了哺乳动物大脑的细胞和遗传复杂性的阻碍。使用简单的整个生物体模型系统具有降低细胞复杂性的优势，同时在生理条件下保持神经元和非神经元连通性。该项目的总体目标是发现非神经元细胞调节神经元激发/抑制平衡的机制。 The roundworm, Caenorhabditis elegans, will be utilized as a model system for four main reasons: 1) its neuronal networks are formed and maintained through mechanisms that are conserved in humans, 2) it has a simple, fully mapped nervous system, 3) it is easy to manipulate through genetic techniques, and 4) it has well-conserved homologs to genes mutated in autism spectrum disorders and epilepsy.这项研究的目标将通过以下特定目的来实现：目标1：确定使用RNA干扰筛查来调节神经元激发/抑制失衡的非神经元细胞中的遗传途径。 AIM 2：在激发/抑制不平衡条件下，利用遗传学方法将神经元与非神经元细胞之间的物理相互作用表征，通过荧光标记细胞相互作用。目标3：确定非神经元细胞的调节是否可以防止自闭症谱系障碍基因突变引起的激发/抑制失衡。该应用的完成将更深入地了解在生理和病理条件下神经元与周围非神经元细胞之间的相互作用。此外，这项研究将发现影响突触功能的神经系统疾病的致病机制，例如自闭症谱系障碍或癫痫。最后，该项目将为治疗自闭症谱系障碍，癫痫和相关神经系统疾病的新型疗法提供潜在的靶标。公共卫生相关性：神经电路活动失衡是许多形式的神经系统疾病的基础，例如自闭症谱系障碍，癫痫和精神分裂症，这些疾病影响了近3％的人群；但是，没有治疗方法或长期疗法。该项目将发现基于神经回路调节的机制，将进一步了解我们对疾病过程的理解，并为将来的治疗提供新的治疗靶标。