Mechanistic understanding of the thermosensitive Transient Receptor Potential (TRP) channels.

瞬时受体电位(Trp)通道是检测和传递物理和化学刺激的跨膜蛋白。它们参与神经系统的各种感觉功能，包括视觉、味觉、痛觉和体温感觉。我的研究项目集中在Trp通道的热敏感家族的分子药理学上，这些家族可以检测热、冷和暖的温度。在分子水平上，Trp通道由四个形成孔的亚基组成，它们聚集在细胞内，并在细胞表面发挥作用，控制细胞外钙穿过质膜的流动。我的长期目标是深入了解调节温度敏感色氨酸通道功能的生物学机制。我们采用多学科方法，包括最先进的成像、电生理学、分子技术来研究这些通道的生物发生和细胞表面表达。我们还旨在了解环境和内源性因素(即激素、细胞因子和神经递质)如何调节这些通道的运输和活动。这项拟议的项目关注的是热敏感的TRPV1通道，该通道也被辣椒素激活，辣椒素是一种从辣椒中提取的“辣”化合物。作为一种钙离子通道，TRPV1参与了特定的钙离子依赖的信号通路，调节感觉加工中的神经元通讯。我们的建议将确定控制TRPV1通道在内质网中组装、运输到质膜并信号传递到调控基因转录的细胞核的钙依赖过程。我们的工作将开发一个框架，以了解热感觉和感觉适应有害的热刺激。这个项目依赖于我作为卡尔加里大学博士后研究员和助理教授获得的大量专业知识和初步数据。我们的发现将为新的研究路线奠定基础，我将利用这些研究路线在一个激励的研究环境中建立一个强大的培训计划。这将为研究生和本科生创造机会，并促进科学知识的发展。

Transient Receptor Potential (TRP) Channels are transmembrane proteins that detect and transduce physical and chemical stimuli. They are involved in various sensory function of the nervous system including vision, taste, pain perception and thermosensation. My research program focuses on the molecular pharmacology of the Thermosensitive families of TRP channel that detect heat, cold and warm temperature. At the molecular level, TRP channels are formed of four pore-forming subunits that assemble into the cell and function at the cell surface to control the flow of extracellular calcium across the plasma membrane. My long term objectives are to gain insight into the biological mechanisms that regulate the function of thermosensitive TRP channels. We employ multidisciplinary approaches including state of the art imaging, electrophysiology, molecular techniques to study the biogenesis and cell surface expression of these channels. We also aim to understand how environmental and endogenous factors (i.e hormones, cytokines and neurotransmitters) modulate the trafficking and the activity of these channels. The proposed project focuses on the heat sensitive TRPV1 channel also activated by capsaicin, the ‘hot’ compound from chili peppers. As a calcium-permeant channel, TRPV1 is involved in specific calcium-dependent signalling pathways that modulate neuronal communication in sensory processing. Our proposal will identify the Ca2+-dependent processes that control TRPV1 channel assembly in the ER, trafficking to the plasma membrane and signalling to the nucleus where gene transcription is regulated. Our work will develop a framework for understanding thermosensation and sensory adaptation to noxious thermal stimuli. This project relies on considerable expertise and preliminary data that I have obtained as a postdoctoral fellow and an assistant professor at the University of Calgary. Our findings will establish a basis for new lines of research which I will use to build a strong training program in a stimulating research environment. This will create opportunities for graduate and undergraduate students and foster the development of scientific knowledge.