甘草次酸激活TMEM16A/CaCCs通道促进上皮细胞Cl-分泌的作用及其分子调控机制

腺上皮是指一些具有分泌功能的上皮细胞，其分泌活动受到氯通道的精细调控。TMEM16A编码的钙激活氯通道（TMEM16A/CaCCs）几乎表达于所有腺上皮，并介导Cl-分泌。TMEM16A/CaCCs开放剂不但可以作为工具药用于研究通道的门控机制、生理功能，还具有用于治疗囊性纤维化、干眼症、口腔干燥症等腺体分泌障碍相关疾病的潜力。然而，目前尚缺乏有效的TMEM16A/CaCCs开放剂。我们前期研究发现甘草次酸类化合物可极大的增强TMEM16A/CaCCs电流。本申请将在这一发现的基础上，深入研究甘草次酸对TMEM16A/CaCCs的开放作用、生物物理学特征，以及相应的分子机制、构效关系；并在多种腺细胞及动物模型上，探讨甘草次酸促进腺上皮分泌的分子基础，评价其治疗效果。此研究将对TMEM16A/CaCCs开放剂的研发、揭示通道的门控机制及囊性纤维化、干眼症、口腔干燥症等疾病的治疗具有重要意义。

Glandular epithelium refers to a number of epithelial cells with secretory functions. Its fluid secretion is elaborately regulated by Cl- channels. TMEM16A encoded Ca2+-activated Cl- channels (TMEM16A/CaCCs) is virtually expressed in all kinds of secretory epithelium, and mediate Cl- secretion. TMEM16A/CaCC openers not only are useful research tools for the gating mechanism and physiological function of TMEM16A/CaCCs, but also are potential drug candidates for the treatment of cystic fibrosis, dry eye syndrome, salivary gland dysfunction and other disorders associated with glandular secretion dysfunction. However, the development of TMEM16A/CaCC openers is not optimistic. Our previous study indicated that glycyrrhetinic acids could be the opener for the recombinant TMEM16A/CaCC currents. Therefore, this project is designed to clarify the effects of glycyrrhetinic acids on TMEM16A/CaCCs and their pharmacological characteristics; the molecular basis and structure-activity relationship; the underlying mechanism of positive effects of glycyrrhetinic acids on epithelial fluid secretion, and evaluates their therapeutic effect in animal models. The research will be of great significance in development of TMEM16A/CaCC openers, revealing the gating mechanism of TMEM16A/CaCCs and new drug discovery in the treatment of diseases such as cystic fibrosis, dry eye syndrome, salivary gland dysfunction.