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有异常性痛觉和机械性痛觉过敏，在这种情况下，无害的触摸刺激现在会引起严重的疼痛。尽管机械转导具有重要的基础意义，但在细胞和分子水平上，它仍然是最不为人所知的信号传导过程之一。触觉是由嵌入皮肤的特殊机械传感器传递的，其中大部分由神经末梢和相关的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尚不清楚。我们的目标是通过利用遗传、分子和生理策略解剖秀丽隐杆线虫机械感觉神经元和神经胶质之间的功能相互作用来理解触觉。具体来说，我假设这种相互作用使用离子通道DELM-1， DEG/ENaC阳离子通道家族的成员，在机械感觉胶质细胞中表达。根据我们的初步结果和对上皮中DEG/ENaC通道作用的了解，我假设需要胶质DELM-1来控制神经元末梢和胶质之间微环境中K+的浓度。初步实验表明，DELM-1受到机械力的抑制。因此，我也假设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DELM-1通道是否调节机械感觉神经元的活动？2) DELM-1是否在胶质细胞和触觉神经元之间的微环境中升高[K+] ？3)胶质DELM-1通道是否具有机械敏感性？在哺乳动物组织中使用皮肤神经准备和冯-弗雷毛发的漂亮工作使我们对触觉的理解取得了重大进展。我现在有了一个前所未有的机会，可以利用以前的工作来探索这个领域的新领域。我的工作可能与我们对相关细胞（包括神经胶质细胞）如何控制整个神经系统神经元功能的理解有关。

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.