络石苷类似物抑制TMEM16A调控肺腺癌发展的分子机制研究

癌症是人类第二大致死疾病，肺癌是对人类健康威胁最大的癌种。发现新的药物靶点，筛选新型靶向药物，揭示癌症发展的分子机制，有助于攻克癌症。本项目以TMEM16A离子通道为研究对象，利用干湿实验相结合的方法从中药天然产物中筛选络石苷类似物TMEM16A抑制剂，比较分析其有效性、安全性和特异性，确认其分子骨架与药效团。藉由分析络石苷类似物小分子与TMEM16A的相互作用力及其产生与传递途径，解析通道门控关闭的生物物理学机制。通过分子、细胞、动物多层次实验结合组学数据分析，构建TMEM16A调控肺腺癌生长信号转导网络，阐明络石苷类似物靶向TMEM16A抑制肺腺癌生长的分子机制。本项目确认TMEM16A可作为肺腺癌治疗新型药物靶标，络石苷类似物可作为肺腺癌靶向药物先导化合物，并明晰其调控通道的生物物理机制与抑制肺腺癌的药理学机理，为以TMEM16A为靶标的新型肺腺癌靶向药物研发提供前期研究基础。

Cancer is the second leading cause of death in humans. Lung cancer is the most serious type of all cancers. In order to cure cancer, we need to discover new drug targets, screen novel targeted drugs and explore the molecular mechanism of cancer development. In this project, we will take TMEM16A ion channel as the research object. The methods combined dry experiments and wet experiments will be taken to screen tracheloside analogues TMEM16A inhibitors from traditional Chinese medicine. The efficacy, safety and specificity of tracheloside analogues will be studied. The molecular skeleton and pharmacophore of tracheloside analogues will be confirmed through compared the molecular structure. The biophysical mechanism of TMEM16A gating closure will be explored by analyzing the interaction between tracheloside analogues to TMEM16A and studying the force generation and transmission pathways. The signal transduction network of lung adenocarcinoma regulated by TMEM16A will be constructed through analyzing molecular, cellular and animal experiments data combined with omics data. In addition, the molecular mechanism of tracheloside analogues inhibit the growth of lung adenocarcinoma targeting TMEM16A will be clarified. This project will confirm that TMEM16A is a new drug target for lung adenocarcinoma. The natural products of tracheloside analogues are lead compounds of lung adenocarcinoma targeted drugs. Moreover, this work will clarify the biophysical mechanism of tracheloside analogues regulating TMEM16A and study the pharmacological mechanism of tracheloside analogues inhibiting lung adenocarcinoma. This project will provide a preliminary research basis for the development of new targeted drugs for lung adenocarcinoma targeting TMEM16A.