TRPV2通道的调节剂与功能研究

TRPV2 channels selectively conduct calcium, and its expression is highest in forebrain and hypothalamus among TRP superfamily. Due to the lack of specific regulators and under-exploration of gating mechanism of TRPV2 channel, we almost know nothing about the roles of TRPV2 role in brain. The project aims to three scientific questions: 1. To design, screen and functional validate TRPV2 channel’s specific modulators, including agonists and inhibitors. 2. To clarify gating mechanism, single channel kinetics and desensitization of TRPV2 channel. 3. To study the role of TRPV2 channel in advanced brain function, such as, cognition, depression, anxiety and relating diseases processes. Our preliminary results support that the project is progressing well. We have verified new agonists and inhibitors of TRPV2 with high efficiency and high selectivity. We have made new progresses in TRPV2’s single-channel characteristics and mechanism of desensitization. Electrophysiological results in hypothalamic brain slice verified the new inhibitor (C32) of TRPV2 channel inhibit the firing rate of action potential. Based on expertise of our research team, with available TRPV2 conditional knockout mice, new regulators and multiple techniques, this project will fulfill our understandings of physiological modulation of TRPV2 and its new roles in mood, cognition, depression, anxiety and relating process.

TRPV2通道通透钙离子，在前脑和下丘脑的表达量在TRP通道超家族中是最高的。由于缺乏专一性的调节剂和对TRPV2通道特性认识不足，目前对TRPV2在脑内的功能机制研究还存在巨大的空白。本项目将研究三个科学问题：1 设计、筛选和确证TRPV2通道特异性的调节剂，包括激动剂和抑制剂。2 阐明TRPV2的门控机制、单通道特性和脱敏机制。3 研究TRPV2通道在脑的高级功能、情绪及抑郁焦虑等疾病过程中的作用。本项目各项前期结果进展良好，已经获得高效高选择性的TRPV2调节剂（激动剂和抑制剂），在TRPV2的单通道特征和脱敏机制方面取得了新进展。开展了下丘脑的脑片电生理研究，发现TRPV2通道抑制剂C32对动作电位有显著的影响。结合TRPV2基因敲除小鼠、新型调节剂和多种技术，研究队伍的专业特长能够确保本项目的顺利实施，最终阐明TRPV2的生理调控机制和在情绪、认知、抑郁焦虑等高级功能中的作用。

针对TRPV2通道缺乏专一性的调节剂和对TRPV2通道特性认识的不足与空白，本项目主要研究三方面的科学内容：1.设计、筛选和确证TRPV2通道特异性的调节剂。2.阐明TRPV2的构效关系和调控机制。3.研究TRPV2通道在脑的高级功能、情绪及抑郁焦虑等疾病过程中的作用。本项目各项结果进展良好，已经获得高效高选择性的TRPV2调节剂，开展了详细的药物靶标和构效关系研究；并结合TRPV2基因敲除小鼠、新型调节剂和多种技术，对TRPV2的生理和药理调控机制以及在抗抑郁焦虑和认知功能等方面进行了多方位的研究和探索，为今后的TRPV2的神经机制研究和新药研发提供了实验依据。