三维组织化肝细胞模型反映非诺贝特的体内作用生物化工专业论文.docxVIP

浙江大学硕士学位论文A 浙江大学硕士学位论文 Abstract Hyperlipemia has become a common disease due to the greatly improved living condition． As hyperlipemia has been the major risk factor of atherosclerosis，people paid great attention to develop lipid—lowering drugs．Lipid metablism is mainly processed in liver where lipid lowering drugs regulate lipid metabolism and trigger hepatotoxicity．Therefore，liver is the focused organ to evualate the pharmacology and toxicity during the discovery process of lipid lowering drugs． As in vivo experiments on animals are often high cost and time-consuming，suitable in vitro models urgently needed as tool to screen lipid—lowering drugs in the early period of development．Currently,in vitro models of hepatocytes include sandwich,spheroids，monolayer culture and SO on．But shortcomings can not be avoided in these models．For example，sandwich cultured hepatocytes lacks the structure of intercelluar junctions，while spheroid model is hard to prepare and poor reproducible．The monolayer culture model is widely used in the culture of hepatocytes in vitro．This model is easy to operate and has good repeatability．However,lipid metabolism in monolayer cultured hepatocytes is quite different仔om liver due to the lack of similar micro—environment in vivo，Moreover,monolayer cultured hepatocytes are not sensitive to the toxicity and effects of drugs．Nevertheless，gene expression related in lipid metabolism in monolayer and sandwich cultured liver cells is quite different from in vivo situation． In order to overcome the defects of monolayer model,gel-entrapment model was used tO analyze the lipid metabolism,as well私the pharmacology and toxicity of a classical lipid—lowering drugufenofibrate(FF)in this thesis．Micro-environment in gel-entrapped model is close to in vivo condition,and this model Can maintain cell functions for a long time．This thesis verified the reliability ofthis model via comparison with the monolayer culture model and laid the groundwork for the pharmacology