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

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的回路功能将对此类疾病的治疗产生深远的影响。除了神经元之外，大脑还含有近十倍的非神经元胶质细胞，它们支持神经元功能并调节兴奋/抑制平衡。哺乳动物大脑的细胞和遗传复杂性阻碍了哺乳动物模型系统的研究。使用简单的整体生物体模型系统具有降低细胞复杂性，同时在生理条件下保持神经元和非神经元连接性的优点。该项目的总体目标是揭示非神经元细胞调节神经元兴奋/抑制平衡的机制。线虫（秀丽隐杆线虫）将被用作模型系统，主要有四个原因：1）其神经元网络是通过人类保守的机制形成和维持的，2）它有一个简单的、完全映射的神经系统，3）它很容易通过遗传技术进行操纵，4）它与自闭症谱系障碍和癫痫症中突变的基因具有高度保守的同源性。本研究的目标将通过以下具体目标来实现：目标 1：使用 RNA 干扰筛选来识别非神经元细胞中调节神经元兴奋/抑制失衡的遗传途径。目标 2：利用遗传方法荧光标记细胞相互作用，表征兴奋/抑制失衡条件下神经元和非神经元细胞之间的物理相互作用。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兴奋/抑制失衡。该应用的完成将有助于更深入地了解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，这项研究还将揭示影响突触功能的神经系统疾病（例如自闭症谱系障碍或癫痫）的致病机制。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疗法提供潜在目标。公共健康相关性：神经回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，影响着近 3% 的人口；然而，没有治愈方法或长期疗法。该项目将揭示神经回路调节的机制，进一步阐明我们对疾病过程的理解，并为未来的治疗提供新的治疗靶点。