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

• 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
• 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

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(申请人提供)：许多神经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，大脑中还含有近十倍数量的非神经元胶质细胞，这些细胞支持神经元功能，调节兴奋/抑制平衡。哺乳动物大脑的这种细胞和遗传复杂性阻碍了对哺乳动物模型系统的研究。使用简单的整体生物模型系统具有降低细胞复杂性的优点，同时在生理条件下保持神经元和非神经元的连通性。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。线虫秀丽线虫将被用作模型系统，主要有四个原因：1)它的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、完整的神经系统，3)它很容易通过基因技术进行操作，以及4)它与自闭症谱系障碍和癫痫中突变的基因具有很好的保守性同源物。这项研究的目标将通过以下具体目标来实现：目标1：利用RNA干扰筛选确定非神经细胞中调节神经元兴奋/抑制失衡的遗传途径。目的2：利用荧光标记细胞相互作用的遗传学方法，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。目的3：确定非神经细胞的调节是否能防止自闭症谱系障碍基因突变引起的兴奋/抑制失衡。这一应用的完成将使人们更深入地了解神经元与周围非神经元细胞在生理和病理条件下的相互作用。此外，这项研究将揭示影响突触功能的神经疾病的致病机制(S)，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、癫痫和相关神经疾病的新疗法提供潜在的目标。 与公共卫生相关：神经回路活动失衡是许多形式的神经疾病的基础，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%的人口；然而，没有治愈或长期治疗的方法。该项目将揭示神经回路调节的基础机制，将进一步阐明我们对疾病过程的理解，并将为未来的治疗提供新的治疗靶点。