基于肾上腺素受体相关"肺主宣发"的现代生物学基础及"宣肺解表"药效物质基础研究

Viscera theory is that lung governing ascent and dispersion, regulating breathing movement, transferring nutrients, spreading heat to regulate temperature, and helping the heart to control blood circulation. How to merge the Chinese medicine theory with modern physiology and pathology in scientific interpretation has been the focus for attention. Previous study founded most of the relieving exterior drugs containing adrenergic receptor (AR) related bioactive ingredients, and the connotation of "xunfa" was consistent with physiological function of adrenergic receptor regulated sympathetic postganglionic fibers dominated the organ. Therefore the hypothesis of "Xuanfei" is closely related to AR pathway signal transduction was put forward. Using radiolabeled and chemical biological modified probes, positron emission tomography, cell imaging, and protein target fishing technology were carried out for revealing its correlation; by bioactivity-based UPLC-Q/TOF screening system, identification of natural effective compounds for AR will be achieved rapidly. Around AR subtype selectivity and AR-cAMP-PKA signaling pathway, the potential therapeutic basis and its molecular mechanism will be clarified in this project; combining with related pharmacodynamic evaluation, the expression differences of AR subtypes in chills or fever different symptoms target organ will be evaluated, and aim to reveal the scientific justification for adapting the remedy to the disease; Ultimately, the modern biological basis of pulmonary governing ascent and dispersion will be clarified from a multidimensional perspective.

藏象理论认为肺主宣发：宣散浊气，转输精微，宣发卫气，助心行血。如何将中医理论与现代生物学相结合，用科学数据诠释其内涵一直是关注的焦点。我们前期研究发现：宣肺解表的药物中存在着与肾上腺素受体(AR)相关的药效物质，而肺主宣发的现象又与AR调控的交感神经节后纤维所支配的效应器官的生理功能相吻合。因此本课题提出：肺主宣发与AR受体通路密切相关，希望利用放射标记的宣肺药效成分及其化学生物修饰的分子探针，结合正电子发射断层扫描、细胞定位以及靶点垂钓等手段揭示其关联性；通过Bioactivity based UPLC-Q/TOF筛选平台，实现对"宣肺解表"药效成分的快速鉴定，并围绕AR亚型的选择性以及AR-cAMP-PKA信号通路开展机制研究，阐明其药效物质基础及分子作用机理；通过不同寒热证候靶器官上AR亚型的表达分布差异分析及相关药效学评价，揭示对证施药的科学性，从多维角度诠释肺主宣发的生物学基础。

虽然“肺主宣发肃降”理论已被中医普遍接受，但将传统理论与现代生物学相结合，用现代科学诠释其科学内涵一直存在着争议。本研究建立了从系统生物学到化学生物学的研究策略，对相关经典理论、方药以及所涉及的药效物质基础与生物学机制进行了梳理，并提出了“肺为藏之长” “肺主宣发”的效应与功能可能取决于不同效应器官上所表达的肾上腺素能受体的亚型以及量的差异；苯乙胺类生物碱及其衍生物是其主要的药效物质基础；中医巧妙地选择了不同的天然药效分子实现了相关信号通路的调控，适应了临床治疗的不同需求；β-AR/cAMP/PKA信号通路是“肺主宣发”发挥效应的关键通路之一；“肺主治节”所体现的核心内容与肌球蛋白轻链的磷酸化水平的调控密切相关；方剂配伍能有效地增强肾上腺素能受体相关的多条信号通路之间的串扰，体现了中医针对复杂疾病采用多通路、多靶点综合治疗的优势。本课题利用代表药物和方剂为例，从蛋白靶点、细胞和整体水平验证上述结论，初步揭示了中医药“肺主宣发肃降”理论的科学内涵。