Molecular dissection of glia-neuron interactions

项目摘要 我们的长期目标是了解神经胶质细胞在神经系统健康，衰老和疾病中的分子细节作用。 人类神经系统有大约相等数量的神经胶质细胞和神经元， 这两种细胞类型对神经功能至关重要。神经胶质和神经元之间的一个重要接触部位是 神经元末梢，神经元接收来自其他神经元的输入（中间神经元树突棘）或 感觉感受器末梢（Sensory receptive endings）神经元末端的形状决定了适当的神经元连接， 功能，包括感官知觉、学习和记忆。虽然认识到神经胶质调节 神经末梢的形状和功能，其分子机制仍然不清楚。的确， 神经胶质-神经元相互作用的许多基本原理仍不清楚，例如是否所有的神经胶质-神经元对 使用相同的分子机制相互作用。然而，重要的是要解决这个差距， 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。 老年痴呆症、自闭症、癫痫等疾病，并可能导致神经功能随年龄增长而衰退。 我们建议在体内用C.优雅作为一个强大的， 基因改造的实验平台C.线虫的神经胶质类似于脊椎动物的神经胶质，我们最近的研究 已经验证了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 确定了两种新的分子机制，通过这种机制，神经胶质细胞与神经元相互作用，以调节它们的形状， 功能和相关的动物行为。我们拥有的这些机制的所有分子组件 迄今为止发现的神经胶质细胞广泛表达，表明神经胶质细胞-神经元相互作用的各个方面在进化上是相互作用的。 在物种间是保守的。重要的是，C。线虫神经胶质可用于快速和可重复的遗传和 体内细胞操作。这种操纵的影响可以在多个层次上进行调查， 从分子（遗传，基因组，蛋白质生物化学），细胞生物学（细胞形状，细胞-细胞接触）和电路 （功能成像，映射连接体）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，我们建议解剖神经胶质细胞的相互作用的分子机制 动物时代的细节。为此，我们将结合我们建立的实验平台， 上述技术，与我们最近确定的多个遗传突变体（1）确定如何 多个分子通路共同使单个胶质细胞-神经元对之间的相互作用成为可能;（2）研究 单个神经胶质细胞如何分化相关神经元以不同方式调节它们的机制细节，以及（3） 剖析不同的神经胶质-神经元对相互作用调节神经元功能的机制。 总之，这些研究将建立一个全面的分子框架，神经胶质细胞如何调节 相关神经元的功能贯穿动物的一生。

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.