开展真菌耐药机制研究对开发新型抗真菌药，克服真菌耐药，应对真菌感染具有重要意义。本课题前期研究发现，白念珠菌Rta2p可促进鞘脂转运，稳定脂筏，从而抵抗因唑类药物抑制麦角甾醇合成而对脂筏造成的损害，使真菌对唑类耐药。本课题拟在此基础上，进一步考察Rta2p缺失、抑制CaN通路或TOR通路的P-gp抑制剂，以及其他脂筏破坏剂，是否都能抑制鞘脂转运、合成，破坏脂筏，影响白念珠菌多药耐药蛋白Cdr1p和Cdr2p在脂筏上的定位和活性；同时考察脂筏稳定剂是否可以抑制上述因素对脂筏稳定性和Cdr1p、Cdr2p活性的影响，以验证白念珠菌Rta2p通过转运鞘脂，稳定脂筏，从而保证Cdr1p和Cdr2p在脂筏上的定位，并促进其药物外排活性的耐药性调控新机制。这一机制的阐明也将揭示P-gp抑制剂通过CaN通路或TOR通路抑制鞘脂转运、合成和脂筏稳定性，从而影响P-gp在脂筏上的定位和活性的作用新机制。

As the incidence of deep fungal infection morbidity and mortality increased rapidly in recent years, it’s very meaningful to make a deep comprehension of fungal drug resistance mechanisms, which is helpful for the antifungal drug development. Based on our previous studies on Rta2p, this research will explore how Rta2p influence the stability of lipid rafts, the location of Cdr1p on lipid rafts, the transport activity of Cdr1p and other different types of drugs. The techniques in the experiments above involve the construction of CDR1 over-expression strain and RTA2 deletion/over-expression strain, the preparation of Cdr1p monoclonal antibodies, lipid rafts analysis, confocal laser targeting, rhodamine 123 efflux and so on. Meanwhile, the research is also focused on the regulation of Rta2p and lipid rafts on Cdr1p and fungal drug resistance by the application of CaN pathway inhibitors, TOR pathway inhibitors and statins. This study will reveal the vital role of lipid rafts in the maintenance of Candida albicans drug resistance. Besides, it will contribute to the further drug target validation, new antifungal drug screening model establishment and drug resistance inhibition.