Glia in Touch Sensation

描述（由申请人提供）：我们依靠触觉进行大多数个人和社会活动。许多形式的损伤和炎症都伴随着异常性疼痛和机械性痛觉过敏，在这种情况下，无害的触摸刺激现在会引起剧烈的疼痛。尽管其基本的重要性，机械转导仍然是最不了解的信号转导过程之一，无论是在细胞和分子水平。触觉是由嵌入皮肤中的专门的机械传感器转换的，其中大部分由神经末梢和相关的神经胶质细胞和上皮细胞组成。这些非神经元细胞在触觉中的作用知之甚少。我们的目标是利用遗传学、分子学和生理学的方法，通过解剖C.优雅具体来说，我假设这种相互作用采用离子通道DELM-1，DEG/ENaC家族的阳离子通道，在mechanosensory神经胶质细胞中表达的成员。基于我们的初步结果和什么是已知的DEG/ENaC通道在上皮细胞中的作用，我假设，神经胶质细胞DELM-1是需要控制的神经元末梢和神经胶质细胞之间的微环境中的K+浓度。初步实验表明，DELM-1被机械力抑制。因此，我还假设DELM-1对细胞外K+的控制是高度动态的，有助于机械传感器的适应。本研究的目的是：1）胶质细胞DELM-1通道是否调节机械感觉神经元的活动？2)DELM-1是否升高了神经胶质和触觉神经元之间微环境中的[K+]？3)神经胶质细胞DELM-1通道是机械敏感的吗？在哺乳动物组织中使用皮肤神经准备和Von-Frey毛发的美丽工作使我们对触觉的理解取得了重大进展。我现在有前所未有的机会利用以前的工作来探索该领域的新领域。我的工作可能与我们理解包括胶质细胞在内的相关细胞如何控制整个神经系统的神经元功能有关。

DESCRIPTION (provided by applicant): We depend on the sense of touch for most individual and social activities. Many forms of injuries and inflammation are accompanied by allodynia and mechanical hyperalgesia, conditions in which innocuous touch stimuli now cause severe pain. Despite its fundamental importance, mechanotransduction remains one of the least understood signaling process, both at the cellular and molecular levels. Touch is transduced by specialized mechanosensors embedded in the skin, most of which are composed of nerve endings and associated glial and epithelial cells. The role of these non-neuronal cells in touch sensation is poorly understood. Our goal is to understand touch sensation by dissecting functional interactions between mechanosensory neurons and glia using genetic, molecular and physiological strategies in C. elegans. Specifically, I hypothesize that such interactions employ the ion channel DELM-1, a member of the DEG/ENaC family of cationic channels, expressed in mechanosensory glia. Based on our preliminary results and what is known about the role of DEG/ENaC channels in epithelia, I hypothesize that glial DELM-1 is needed to control the concentration of K+ in the microenvironment between the neuronal ending and glia. Pilot experiments suggest that DELM-1 is inhibited by mechanical forces. Thus, I also hypothesize that the control of extracellular K+ by DELM-1 is highly dynamic and contributes to adaptation of the mechanosensors. The aims of this proposal are: 1) Does the glial DELM-1 channel regulate the activity of mechanosensory neurons? 2) Does DELM-1 elevate [K+] in the microenvironment between glia and touch neurons? 3) Is the glial DELM-1 channel mechanosensitive? Beautiful work in mammalian tissues using skin-nerve preparation and Von-Frey hair has allowed major progress in our understanding of touch sensation. I have now the unprecedented opportunity to capitalize on this previous work to explore a new area in the field. My work is likely to be relevant to our understanding of how associated cells, including glia, control the function of neurons throughout the nervous system.