Glial Control of Neuron Development and Function - Administrative Supplement

神经胶质对神经元发育和功能的控制 - 行政补充

• 批准号: 10632281
• 负责人: Shai Shaham
• 金额: $ 13.96万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632281
• 关键词: Address; Administrative Supplement; Afferent Neurons; Animals; Astrocytes; Biology; Brain; Bypass; Caenorhabditis elegans; Cell Death; Cell Fraction; Complement; Cues; Development; Excitatory Synapse; Goals; Hand; Human; Ions; Learning; Molecular; Nematoda; Nerve Degeneration; Nervous System; Neuroglia; Neuromuscular Junction; Neurons; Neurotransmitter Receptor; Organ; Play; Radial; Sense Organs; Sensory; Shapes; Specific qualifier value; Structure; Synapses; System; Testing; Vertebrates; functional plasticity; gliogenesis; in vivo; information processing; nervous system development; neuron development; neuronal survival; programs; synaptic function; transcription factor

Our long-term goal is to understand how glia contribute to nervous system development, function, and information processing. Glia constitute a large fraction of cells in the vertebrate nervous system and surround neuronal receptive endings to form isolated compartments. Most excitatory synapses are glia-ensheated, as are sensory-neuron receptive endings and neuromuscular junctions. Major gaps remain in our understanding of glia. While developmental specification of some glia has been explored, programs governing astrocyte or sensory organ glia differentation are not clear. How glia form and regulate compartments around synapses and other neuronal receptive endings is also not understood. Glia have been proposed to regulate neuronal activity, yet the effector mechanisms are not fully explored. Finally, neuron structural and functional plasticity may, in part, be under glial control, yet the details are not at hand. Thus, much remains to be learned about glial functions and their underlying molecular programs. In many animals, neurons are born in excess, and the final neuronal complement is determined in part by glial and other secreted cues controlling cell death. Glial manipulation, thus, often leads to neuronal demise. A long-standing goal has been to identify in vivo settings for studying glia-neuron interactions that bypass the neuron-survival problem. We have taken a major step towards this goal by pioneering the nematode C. elegans as a facile and relevant system for studying glia and their nervous system contributions. We showed that C. elegans possess glia, and that these ensheath sensory-neuron receptive endings, highly resembling glial structures found in vertebrates sense organs, as well as envelop the CNS, wrapping around defined synapses. Like vertebrate astrocytes, these latter glia tile, subsuming specific CNS domains, express transcription factors promoting gliogenesis in vertebrates, and express ion and neurotrasmitter transporters, channels, and neurotransmitter receptors. The development of these glia bears uncanny similarities to the radial glia-to-astrocyte developmental transition in vertebrate brain development. Importantly, in C. elegans, neuron survival does not require glia, but glia manipulation results in major deficits in neuron shape and function. C. elegans therefore offers a unique in vivo arena to study glia and their effects on the nervous system. Here we aim to investigate three interrelated aspects of glia-neuron biology. (1) We will determine how astrocytic glia develop and regulate synaptic function. (2) We will determine glia guide brain assembly. (3) We will study a new cell death program resembling glia-dependent neurodegeneration. In addressing these questions we challenge the view that only neurons underlie the phenomena under study, and posit that glia are integral regulators.

我们的长期目标是了解胶质细胞如何促进神经系统发育，功能， 信息处理.神经胶质细胞构成脊椎动物神经系统中的大部分细胞，并且围绕 神经元感受性末梢形成孤立的隔室。大多数兴奋性突触都是胶质包裹的， 是感觉神经元的感受末梢和神经肌肉接头。在我们的理解中仍然存在重大差距 神经胶质细胞。虽然已经探索了一些神经胶质细胞的发育特化，但控制星形胶质细胞或 感觉器官胶质细胞分化尚不清楚。神经胶质如何形成和调节突触周围的隔间， 其他神经元感受性末梢也不清楚。胶质细胞被认为可以调节神经元 活性，但效应机制尚未完全探索。最后，神经元的结构和功能可塑性 可能部分受神经胶质控制，但细节还不清楚。因此，仍有许多需要了解的 神经胶质功能及其潜在的分子程序。在许多动物中，神经元是过量产生的， 最终的神经元补体部分地由控制细胞死亡的神经胶质和其它分泌的信号决定。胶质 因此，操纵常常导致神经元死亡。一个长期的目标是确定体内环境 来研究绕过神经元存活问题的胶质神经元相互作用。我们迈出了重要的一步 为了实现这一目标，我们首先研究了线虫C. elegans作为研究神经胶质的一个简单和相关的系统， 神经系统的贡献。我们证明了C.线虫拥有神经胶质，这些神经胶质包裹着 感觉神经元感受性末梢，与脊椎动物感觉器官中的神经胶质结构非常相似， 也包裹着中枢神经系统，包裹着特定的突触。像脊椎动物的星形胶质细胞一样，后者的胶质细胞， 包含特定的CNS结构域，表达促进脊椎动物神经胶质生成的转录因子，和 表达离子和神经递质转运蛋白、通道和神经递质受体。的发展 这些神经胶质细胞与脊椎动物大脑中放射状神经胶质细胞向星形胶质细胞的发育转变有着惊人的相似之处 发展重要的是，在C。神经元的存活并不需要神经胶质，但神经胶质的操纵会导致 神经元形状和功能的严重缺陷。C.因此，线虫提供了一个独特的体内竞技场来研究神经胶质， 对神经系统的影响在这里，我们的目标是研究胶质神经元的三个相互关联的方面， 生物学(1)我们将确定星形胶质细胞如何发展和调节突触功能。(2)我们将确定 神经胶质引导大脑组装。(3)我们将研究一种新的细胞死亡程序， 神经变性在解决这些问题时，我们挑战了只有神经元才是神经元的基础的观点。 正在研究的现象，并重申神经胶质是不可或缺的调节器。