基于“多组学-多通路”的天然药物J06改善高尿酸血症的药效及分子机制

高尿酸血症为核酸代谢紊乱导致的慢性疾病，已成为我国仅次于糖尿病的第二大代谢性疾病，患者常伴痛风、慢性肾病等并发症需终身服药，目前临床缺乏安全、有效的治疗药物。前期我们从临床上发现天然药物J06可下调高血脂症病人血尿酸；而高尿酸血症小鼠药效学实验验证了J06疗效显著并可保护肾脏，作用机制与其抑制尿酸代谢通路AMPD2蛋白表达有关，但可能存在多通路协同作用，机制尚未明了。因此，本课题围绕天然药物J06改善高尿酸血症的药效及作用机制的科学问题，采用多组学技术（代谢组学、基因组学等）结合高灵敏高分辨的分析方法，通过开展J06体内药代动力及药效评价，完成多通路模式的机制研究。主要包括：尿酸代谢通路上的AMPD2蛋白、肠道或肾脏的尿酸转运体、肠道菌参与尿酸的分解等，旨在阐明J06改善高尿酸血症的分子机制，为从我国原创的天然药物中寻找和发现安全、有效的改善高尿酸血症的治疗药物提供重要的科学依据。

Hyperuricemia is a chronic disease caused by nucleic acid metabolism disorder, and has become the second largest metabolic disease in China after diabetes. Patients often suffer from gout, chronic kidney disease and other complications requiring lifelong medication. Currently, there is a lack of safe and effective drug. In the early stage, we found that natural medicine J06 can down-regulate blood uric acid in patients with hyperlipidemia. The pharmacodynamics experiment of hyperuricemia mice verified that J06 has significant curative effect and can protect the kidney, and its mechanism of action inhibits the expression of AMPD2 protein in uric acid metabolism pathway. But there may be multi-channel synergy, the mechanism is not yet clear. Therefore, this topic focuses on the scientific problem of improving the efficacy and mechanism of hyperuricemia with natural medicine J06, using multi-omics technology (metabnomics, genomics, etc.) combined with high-sensitivity and high-resolution analysis methods, through the implementation of J06 in vivo pharmacokinetic and pharmacodynamic evaluation, complete the mechanism study of multi-channel mode. It mainly includes: AMPD2 protein in uric acid metabolic pathway, uric acid transporter in intestinal or kidney, intestinal bacteria involved in the decomposition of uric acid, etc., aiming to elucidate the molecular mechanism of J06 in improving hyperuricemia, which is from the original natural medicine in China. It provides important scientific evidence for discovering safe and effective drugs to improve hyperuricemia.