血管生成调控基因Adcyap1b介导头孢菌素诱发血管损伤的作用及机制研究

药品不良反应不仅与活性药物成分的理化性质和毒性有关，也与药品中的杂质密切相关。前期研究发现，C3位含甲巯四氮唑（MTT）的头孢菌素导致血管损伤与血管生成障碍有关，并可抑制斑马鱼血管生成调控基因adcyap1b表达。在此基础上，本项目拟以“adcyap1b基因介导的血管生成”为新切入点，以血管特异性转基因荧光斑马鱼为研究载体，利用系统毒理学研究策略，采用转录组测序、生物信息学、显微拉曼光谱成像、分子生物学、计算机模拟等技术，通过检测药物/杂质对血管形态、功能、基因、信号通路的影响，考察头孢菌素的血管毒性作用和机制，提出并验证假说：adcyap1b基因在VEGF及相关信号通路调控的血管生成中发挥重要作用，C-3位含有MTT的头孢菌素通过抑制adcyap1b表达，干扰血管生成，诱发血管损伤，导致血管毒性。本项目可为药物/杂质的毒性及机制评价、化学药品中杂质的质量控制及临床用药提供理论和实验依据。

The adverse reactions of drug products may be related to the drug itself and the wide range of clinical use. Drug impurities can also impact safety. Previously, we found that 1-methyl-1H-tetrazole-5-thiol (MTT) in the C-3 substituent of cephalosporins induced vascular damage and inhibited the expression of angiogenesis regulatory gene adcyap1b. We hypothesize that adcyap1b plays an important role in angiogenesis via vascular endothelial growth factor signaling pathway, and cephalosporins with a MTT at the C-3 position may regulate the expression of adcyap1b gene leading to abnormal angiogenesis and vascular damage. This study will apply transcriptome analysis, bioinformatics, Raman mapping, and molecular docking that may have utility in understanding the molecular mechanism of vascular toxicity. Overall, the information detailed here can identify the molecular mechanism of drug and impurity toxicity, which is a key requirement for drug safety assessment and quality control.