白念珠菌开关蛋白Sfl1和Sfl2在菌丝发育和致病过程中的调控机制研究

Candida albicans is the most frequently isolated opportunistic pathogen of humans. Important to its pathogenesis is its ability to switch between different morphological forms. C. albicans has evolved many mechanisms to modulate cell morphology in response to different environmental conditions. The C. albicans morphogenesis is associated with many transcriptional factors, which play negative or positive regulatory roles. We previously reported two heat shock factor-type (HSF) transcription factors (Sfl1 and Sfl2) that antagonistically controlled morphogenesis in C. albicans. Although they are homologous HSF containing transcriptional regulators, Sfl1 acts as a repressor in, whereas Sfl2 acts as an activator in filamentous growth. Both Sfl1 and Sfl2 could bind to the promoter of at least 113 common targets through divergent binding motifs and modulated directly the expression of key transcriptional regulators. The binding of Sfl1 and Sfl2 to their targets occurs with the co-binding of Efg1 and/or Ndt80. Our aim in this research will be (1) study the synergistic roles of Sfl1 and Sfl2 together with Efg1 during hyphal development of C. albicans; (2) identification of virulent factors associated with Sfl1 and Sfl2 in pathogenesis of C. albicans; (3) study the synergistic roles of Sfl1 and Sfl2 together with Ndt80 in drug resistance of C. albicans; (4) identification of potential drug resistance targets associated with Sfl1 and Sfl2 by using Hsp90 specific inhibitors. Our long-range goal is to understand the molecular mechanisms of Sfl1 and Sfl2 act as central ‘‘switch on/off’’ regulators to coordinate the regulation of morphogenesis, pathogenesis and drug resistance via different targets in C. albicans.

白念珠菌的形态发生受多个转录因子调控，发挥着正调控作用或负调控作用。我们鉴定了两个功能相反的调控因子Sfl1和Sfl2，在菌丝发育中起中央开关作用。Sfl1和Sfl2的N-端都含有保守的HSF结构域，能结合于113个靶基因，而且与Efg1和Ndt80结合的区域有重叠。我们打算深入研究Sfl1和Sfl2调控不同靶基因启动子的分子机制，分析Sfl1和Sfl2与其它转录因子以及染色质修饰复合物的协同作用。确定Sfl1和Sfl2与Efg1的相互作用，在白念珠菌菌丝发育和致病过程中，研究它们协同应答不同外界刺激调控下游靶基因启动子的规律。分析Sfl1和Sfl2与Ndt80的协同作用以及在白念珠菌耐药过程中的作用方式，利用Hsp90特异性抑制剂筛选分析协同Hsp90耐受抗真菌药物的新靶点。阐明开关蛋白Sfl1和Sfl2通过对不同靶基因表达的开与关进而调控白念珠菌菌丝发育、致病和耐药的分子机制。