人内源性多肽与T细胞钾通道Kv1.3相互作用的发现及功能机制研究

In human body, about 100 ubiquitous potassium channels play important roles in the physiological and pathological activities. For example, the potassium channel Kv1.3 in T cells is closely related to the autoimmune diseases and has been the target of new drugs. Different human potassium channels (as a kind of shield) are widely inhibited by peptide toxins (as a kind of spear) from venomous animals, such as scorpions and snakes. However, whether there is an endogenous peptide inhibitor of potassium channels in an individual human or other mammalian remains a question so far. Based on the our systematic work of toxin peptide-potassium channel interactions, this project will focus on the key scientific question of interactions between human endogenous peptides and potassium channel Kv1.3 in T cells and their binding mechanisms, and carry out following work: Screening and identifying interactions between human endogenous peptides and potassium channel Kv1.3 in T cells; Investigating the effects of human endogenous peptide-Kv1.3 channel interactions on cytokine secretion in T cells; Revealing the molecular mechnism of endogenous peptide-potassium channel Kv1.3 interactions. All these studies will reveal the natural phenomenon of interdependent relationship between endogenous peptides (as a kind of spear) and potassium channels (as a kind of shield)in the human body, find the novel immune modulation functions of endogenous peptides acting on potassium channel Kv1.3 in T cells, and open a new field of discovery of endogenous peptides acting on potassium channels and their research and application.

约100种人源钾通道分布广泛并发挥重要生理病理功能，如T细胞钾通道Kv1.3与自身免疫疾病密切相关并成为新药研发靶标。不同人源钾通道（作为"盾"）的电流广泛地被有毒动物（如蝎、蛇等）毒液中毒素多肽（作为"矛"）所抑制，但在人和其它哺乳动物体内是否存在抑制钾通道电流的内源性多肽仍是一个未解之谜。基于课题组在动物毒素多肽与钾通道相互作用的系统工作积累，本项目围绕"人内源性多肽与T细胞钾通道Kv1.3的相互作用及功能机制"关键科学问题，拟创新开展：筛选与鉴定人内源性多肽与T细胞钾通道Kv1.3的相互作用；研究内源性多肽与钾通道Kv1.3相互作用对T细胞的细胞因子分泌影响；揭示内源性多肽与钾通道Kv1.3作用的分子机制。这些工作将揭示人体内源性多肽（"矛"）与钾通道（"盾"）相互依存的自然现象，发现内源性多肽作用T细胞产生新的免疫调节功能与机制，开辟作用钾通道内源性多肽的发现及其功能机制研究的新领域。

防御素多肽广泛分布于真菌、植物、无脊椎动物、脊椎动物，是一类重要的天然多肽资源。在结构和分子性质上它们与作用钾离子通道的动物神经毒素具有一定的相似性，但它们是否能够调节钾离子通道仍是一个未知的科学问题。基于课题组在动物毒素多肽与钾通道相互作用的系统工作积累，本项目围绕“人内源性多肽与T 细胞钾通道Kv1.3 的相互作用及功能机制”关键科学问题，创新开展了筛选与鉴定人内源性多肽与T 细胞钾通道Kv1.3 的相互作用研究，发现了系列人源防御素多肽（hBD1, hBD2, hBD3, hBD4, HNP1, HD5等）选择性作用钾离子通道Kv1.3，并能够调节细胞因子IL-2的分泌。在分子作用机制方面，实验发现大部分人源防御素多肽（防御素多肽HD5，及β防御素多肽hBD1、hBD3、hBD4）采用经典的多肽与钾离子通道相互作用模式，即识别钾离子通道细胞外的孔区部分。少量多肽（如防御素多肽HNP1和hBD2）不仅能够识别钾离子通道Kv1.3细胞外的孔区部分，而且能够识别钾离子通道Kv1.3跨膜螺旋S1-S2细胞外的linker。在此基础上，本项目进一步发现了作用钾离子通道 的真菌和无脊椎动物青来源的防御素多肽。这些工作不仅揭示人体内源性多肽（“矛”）与钾通道（“盾”）相互依存的自然现象，发现内源性多肽作用T 细胞产生新的免疫调节功能与机制，而且证明了不同类型物种来源的防御素是一类钾离子通道新型调节剂，从而开辟作用钾通道防御素多肽的发现及其功能机制研究的新领域。