肾阳虚证与衰老及诸多疾病关系密切，是影响现代人生存质量的一大因素，右归丸是治疗肾阳虚的代表方，阐明其作用机制有利于揭示其科学价值。课题组前期研究发现：①肾阳虚时神经内分泌免疫系统生物分子网络平衡被破坏，且生物分子很少单独作用，而是通过网络交互作用而影响生物系统的功能；②右归丸药效优于肾气丸、右归饮等，会引起机体多个生物分子不同程度的回调。由此提出假说：右归丸通过生物分子网络对机体整体调节。因此本课题在前期研究基础上，将与肾阳虚证相关的神经内分泌生物分子和代谢标志物通过代谢通路连接构建多维立体的肾阳虚证生物分子网络。建立随时间变化的右归丸复方拆方调节肾阳虚早、中、晚期的动物模型，利用支持向量回归机对非线性系统良好的逼近能力探讨右归丸干预状态大鼠肾阳虚证生物分子网络的相互关系，探寻右归丸调节肾阳虚的关键作用靶点，阐明右归丸调节肾阳虚的生物学机制，为复方配伍规律研究以及中药新药研发提供思路借鉴。

Kidney-yang deficiency is associated with senescence and many diseases closely and it is a major factor affecting the quality of life of modern people. Yougui Pill is a classical formula for treating kidney-yang deficiency. Clarifying its mechanism could reveal its scientific value better. Our previous research indicating that the balance of biomolecular networks of neuroendocrine immune system were destroyed in kidney-yang deficiency, and the biological molecules rarely effect alone, but tend to effect in group, to affect the function of the biological system through the interaction of the network. The efficacy of Yougui Pill was better than Shenqi Pill and Yougui Drink. It can reduce kidney-yang deficiency by regulating multi-targets in the body. Thus we propose hypothesis: Yougui Pill could regulate the body as a whole through biomolecular networks. Based upon the former research this project will form a multidimensional biomolecular network of kidney-yang deficiency syndrome by connecting the biological molecules in neuroendocrine immune system and metabolic markers of kidney-yang deficiency through metabolic pathways. Then establish a early, middle and late period (time-varying) animal model of regulating kidney-yang deficiency with Yougui Pill. We will explore the interactions between biomolecules in biomolecular network of kidney-yang deficiency syndrome under intervention of Yougui Pill by using support vector regression machine which has good approximation to nonlinear systems, explore the interactions between the biological molecules in neuroendocrine immune system and metabolic markers especially, locate the target biomolecules, and to clarify the biological mechanisms of kidney-yang deficiency regulation with Yougui Pill. This research could also provide ideas and references to the research of compatibility law on formula and the development of new drug in traditional Chinese medicine.

肾阳虚证与衰老及诸多疾病关系密切，是影响现代人生存质量的一大因素，右归丸是治疗肾阳虚的代表方，阐明其作用机制有利于揭示其科学价值。本课题建立了随时间变化的右归丸复方拆方调节肾阳虚早、中、晚期的动物模型：①利用支持向量回归机对非线性系统良好的逼近能力探讨肾阳虚证生物分子网络的相互关系，发现垂体-靶腺轴生物分子之间的相互调控失衡，尤其是垂体-肾上腺轴的枢纽作用失效是肾阳虚的发病机制之一。②对肾阳虚证进行了分时期的基于核磁共振的代谢组学研究，找出了肾阳虚证的代谢标志物并进行了通路分析，已经鉴定了17种显著变化的代谢物，包括乳酸盐、缬氨酸、丙氨酸、蛋氨酸、琥珀酸盐、谷氨酰胺、3-羟基丁酸盐、肌酸、胆碱、HDL、LDL、VLDL、TMAO、甜菜碱、酪氨酸、柠檬酸盐和甘油。这些变化与能量代谢紊乱、氨基酸代谢、脂质代谢、胆碱代谢和肠道代谢有关。③利用网络药理学发现右归丸包含61种活性化合物。这些化合物可能对3177种靶蛋白产生影响，涉及23种通路；利用代谢组学分析，发现22内源性代谢标志物，这些代谢标志物主要参与10种代谢通路，这些活性化合物主要对8种靶蛋白产生影响。结合网络药理学和代谢组学，我们发现右归丸调节肾阳虚主要是与右归丸中的5种中药材的19种活性成分相关。发现右归丸调节肾阳虚主要与能量代谢、氨基酸代谢、炎症反应、细胞凋亡、氧化应激和肠道菌群的代谢有关。④利用支持向量回归机模型探究了右归丸的配伍规律，发现右归丸中补阴药和补阳药之间具有协同作用；同时右归丸的边缘药对补阴药有促进作用，尤其是其中熟地当归药对之间协同作用较强。通过本课题的研究，探寻了右归丸调节肾阳虚的关键作用靶点，初步阐明了右归丸调节肾阳虚的生物学机制，可以为复方配伍规律研究以及中药新药研发提供思路借鉴