Molecular dissection of glia-neuron interactions

胶质神经元相互作用的分子解剖

• 批准号: 10269028
• 负责人: Aakanksha Singhvi
• 金额: $ 21.37万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269028
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Animal Behavior; Animals; Binding; Biological Assay; Brain; Caenorhabditis elegans; Cell Shape; Cells; Cellular biology; Code; Cues; Dendritic Spines; Disease; Disease model; Dissection; Environment; Epilepsy; Functional Imaging; Future; Genes; Genetic; Genetic Models; Genomics; Goals; Health; Health system; Hermaphroditism; Human; Impairment; Individual; Instruction; Interneurons; Kinetics; Learning; Logic; Longevity; Maps; Memory; Modeling; Molecular; Molecular Genetics; Monitor; Nervous System Physiology; Nervous system structure; Neuroglia; Neurons; Neurophysiology - biologic function; Parkinson Disease; Pathway interactions; Perception; Property; Protein Biochemistry; Reproducibility; Research; Resolution; Role; Sensory; Shapes; Site; Specific qualifier value; Specificity; Speed; Study models; System; Techniques; Testing; age related; autism spectrum disorder; cell type; cellular imaging; combinatorial; connectome; in vivo; information processing; mutant; nervous system disorder; neural circuit; novel; proteostasis; relating to nervous system; sex; tool

PROJECT SUMMARY Our long-term aim is to understand glial roles in nervous system health, aging and disease in molecular detail. The human nervous system has about equal numbers of glia cells and neurons, and interactions between these two cell types is critical for neural functions. An important site of contact between glia and neurons is the neuron-ending, where neurons receive input from other neurons (interneuron dendritic spine) or the environment (sensory receptive-endings). Neuron-ending shape dictates appropriate neuron connectivity and functions, including sensory perception and learning and memory. While it is appreciated that glia modulate neuron-ending shapes and functions, molecular mechanisms underlying this remain poorly defined. Indeed, many fundamental principles of glia-neuron interactions remain unclear, such as whether all glia-neuron pairs interact using identical molecular mechanisms. It is however important to address this gap in our understanding of glial functions, because impaired glia-neuron interactions are implicated in many neurological diseases such as Alzheimer’s disease, Autism, epilepsy and may contribute to neural decline with age. We propose to dissect glia-neuron interactions in molecular detail in vivo, using C. elegans as a powerful and genetically amenable experimental platform. C. elegans glia resemble vertebrate glia, and our recent studies have validated this as a powerful setting to rapidly probe glia-neuron molecular interactions. We previously identified two novel molecular mechanisms by which glia interact with neurons to regulate their shape, functions and associated animal behaviors. All molecular components of these mechanisms that we have uncovered so far are broadly expressed, suggesting that aspects of glia-neuron interactions are evolutionarily conserved across species. Importantly, C. elegans glia are accessible for rapid and reproducible genetic and cellular manipulations in vivo. Effects of such manipulation can be investigated at multiple levels of inquiry, from molecular (genetic, genomic, protein biochemistry), cell-biology (cell shape, cell-cell contacts) and circuits (functional imaging, mapped connectome) to animal behavior and aging studies, and disease models (Alzheimer’s, Parkinson’s). Here, we propose to dissect molecular mechanisms of glia-neuron interactions throughout animal age in detail. For this, we will couple the experimental platform we established, and techniques described above, with the multiple genetic mutants we recently identified to (1) determine how multiple molecular pathways together enable interactions between a single glia-neuron pair; (2) investigate in mechanistic detail how a single glia can differentiate associated neurons to regulate them differently, and (3) dissect mechanisms by which different glia-neuron pairs interact to regulate neuron functions with age. Together, these studies will build a comprehensive molecular framework of how a glia cell modulates the functions of associated neurons throughout animal an animal’s lifespan.

项目概要 我们的长期目标是从分子细节上了解神经胶质细胞在神经系统健康、衰老和疾病中的作用。 人类神经系统有大约相同数量的神经胶质细胞和神经元，并且它们之间的相互作用 这两种细胞类型对于神经功能至关重要。神经胶质细胞和神经元之间的重要接触部位是 神经元末梢，神经元接收来自其他神经元（神经元间树突棘）或神经元的输入 环境（感觉接受结局）。神经元末端形状决定了适当的神经元连接和 功能，包括感觉知觉、学习和记忆。虽然人们认识到神经胶质细胞调节 神经元末端的形状和功能，其背后的分子机制仍然不明确。的确， 神经胶质细胞-神经元相互作用的许多基本原理仍不清楚，例如是否所有神经胶质细胞-神经元对 使用相同的分子机制相互作用。然而，解决我们的这一差距非常重要。 了解神经胶质功能，因为受损的神经胶质-神经元相互作用与许多神经系统疾病有关 阿尔茨海默病、自闭症、癫痫等疾病，并可能导致神经随着年龄的增长而衰退。 我们建议使用秀丽隐杆线虫作为强大的、 适合遗传的实验平台。线虫神经胶质类似于脊椎动物神经胶质，我们最近的研究 已验证这是快速探测神经胶质-神经元分子相互作用的强大设置。我们之前 确定了神经胶质细胞与神经元相互作用以调节其形状的两种新分子机制， 功能和相关的动物行为。我们拥有的这些机制的所有分子成分 迄今为止发现的内容被广泛表达，表明神经胶质-神经元相互作用的各个方面是进化的 跨物种保守。重要的是，线虫神经胶质细胞可用于快速且可重复的遗传和 体内细胞操作。这种操纵的影响可以在多个层面进行调查， 来自分子（遗传、基因组、蛋白质生物化学）、细胞生物学（细胞形状、细胞间接触）和电路 （功能成像、映射连接组）到动物行为和衰老研究以及疾病模型 （阿尔茨海默氏症、帕金森氏症）。在这里，我们建议剖析胶质神经元相互作用的分子机制 整个动物时代的详细信息。为此，我们将结合我们建立的实验平台， 如上所述的技术，利用我们最近鉴定的多个基因突变体来（1）确定如何 多个分子途径共同实现单个神经胶质细胞对之间的相互作用； (2) 调查 单个神经胶质细胞如何区分相关神经元以对其进行不同的调节的机制细节，以及 (3) 剖析不同神经胶质细胞对相互作用以随年龄调节神经元功能的机制。 这些研究将共同​​构建一个关于神经胶质细胞如何调节 动物整个生命周期中相关神经元的功能。