Glial ion channels in glia/neurons interactions

项目总结 触摸对于我们的生存和社会纽带是必不可少的，在许多形式的伤害和破坏中，触摸是必不可少的 疾病状态。尽管它的基本重要性，触摸转导仍然是最不被理解的之一。 细胞和分子水平的信号传递过程。触觉是由嵌入在体内的感受器介导的 皮肤，大部分由神经末梢和附属神经胶质细胞或上皮细胞组成。开创性 对哺乳动物默克尔细胞复合体的研究表明，上皮细胞，而不是神经元， 主要的感觉细胞。然而，人们对神经胶质细胞对其他触觉功能的贡献知之甚少。 受体，包括帕西尼小体和迈斯纳小体。如果发现触觉感受器的神经胶质细胞能够感知和 作为机械力传递的中介，这一发现将构成范式转变，并可能表明 这些细胞作为治疗触觉中断条件的新靶点。我的实验室已经致力于 在过去的16年里，利用先驱模式生物秀丽线虫对胶质细胞/神经元串扰进行了研究。我们 发现蠕虫鼻子触摸感受器复合体的两性胶质细胞(AMSH)通过增加 细胞内钙离子和氯离子。这些结果表明，Amsh胶质细胞可能被赋予了检测 机械力。此外，我们还发现Amsh神经胶质细胞的钙离子反应在时间上先于神经元的钙离子反应。 反应，增加了神经胶质细胞可能是主要感觉细胞的有趣可能性。这样做的目的是 建议利用线虫的遗传学，体内的钙离子和氯离子成像工具，以及直接的行为 从基因到行为、神经胶质细胞机械敏感性和神经胶质细胞/神经元串扰的分析 触觉感受器。我们相互关联但相互独立的目标是：1)确定是什么在体内介导了钙离子的瞬变 触摸刺激下的AMSH胶质细胞及其在触摸中的功能；2)识别神经胶质细胞/神经元的机制 触摸感受器中的串扰，以及3)确定是什么介导了触摸时Amsh胶质细胞氯离子的变化 刺激及其在触摸中的作用。哺乳动物的开创性工作促进了我们对触摸的理解 轰动一时。然而，从皮肤获取触摸感受器的困难阻碍了这一进展 以及哺乳动物系统的复杂性。我现在有一个前所未有的机会来利用这一点。 之前的工作是使用遗传上更容易驯化的模型C来探索该领域的新领域。 优雅女装。我的工作可能会揭示神经胶质细胞功能和神经胶质细胞/神经元串扰的一般原理 其他感觉系统和神经系统的其他部分。

PROJECT SUMMARY Touch is essential for our survival and for social bonding, and in disrupted in many forms of injuries and disease states. Despite its fundamental importance, touch transduction remains one of the least understood signaling processes, both at the cellular and molecular levels. Touch is mediated by receptors imbedded in the skin, most of which are composed of nerve endings and accessory glial or epithelial cells. Groundbreaking work on the mammalian Merkel cells complex demonstrated that the epithelial cell, rather than the neuron, is the primary sensory cell. However, little is known about the contribution of glia to the function of other touch receptors, including the Pacinian and Meissner’s corpuscles. If glia of touch receptors are found to sense and mediate the transduction of mechanical forces, this finding would constitute a paradigm shift and may suggest these cells as novel targets for the treatment of conditions in which touch is disrupted. My lab has dedicated the last 16 years to the study of glia/neuron cross talk using the pioneering model organism C. elegans. We found that Amphid glial cells (Amsh) of the worm nose touch receptor complex respond to touch by rise of intracellular Ca2+ and Cl-. These results suggest that Amsh glia may be endowed with mechanisms that detect mechanical forces. Furthermore, we found that Ca2+ responses in Amsh glia temporally precede neuronal Ca2+ responses, raising the intriguing possibility that glia might be the primary sensory cells. The goal of this proposal is to leverage C. elegans genetics, in vivo Ca2+ and Cl- imaging tools, and straightforward behavioral assays to dissect from gene to behavior glial mechanosensitivity and glia/neuron cross talk in the worm nose touch receptor. Our inter-related but independent aims are: 1) To determine what mediates Ca2+ transients in Amsh glia upon touch stimulation and their function in touch, 2) To identify mechanisms of glia/neuron crosstalk in touch receptors, and 3) To determine what mediates Amsh glial Cl- changes upon touch stimulation and their function in touch. Pioneering work in mammals has advanced our understanding of touch sensation. However, progress has been hindered by the difficulty of harvesting touch receptors from the skin and the complexity of the mammalian system. I have now the unprecedented opportunity to capitalize on this previous work to explore a new area in the field using the genetically amenable and more tractable model C. elegans. My work is likely to reveal general principles of glial function and glia/neuron crosstalk relevant to other sensory systems and other parts of the nervous system.