Regulation of mitosis and morphogenesis in the fungal pathogen Candida albicans

我的研究重点是真核细胞周期进程和形态发生的调控。这些过程中的缺陷对细胞增殖、发育和癌症有着至关重要的影响。 我们正在专门研究人类重要的真菌病原体白色念珠菌的有丝分裂和形态发生的调节。C.白色念珠菌可以在酵母、假菌丝和极化菌丝细胞之间转换。这种行为对于发病机制至关重要;锁定在一种形式中的细胞失去毒性。酵母到菌丝的转换受环境因素的调节，但其机制尚未完全了解。C.细胞周期和细胞增殖的调控白色念珠菌就更不清楚了 我们对C.包括polo样激酶Cdc 5 p和后期促进复合物/环体的激活剂在内的白色念珠菌，与其他真菌相比显示出不同的特征，表明有丝分裂回路中的重新布线。我们还证明了细胞周期信号深刻地影响形态发生。酵母有丝分裂停滞导致高度极化的细胞，在许多方面不同于真正的菌丝，但在以后的生长阶段表达几个菌丝毒力基因。 相比之下，通过类似的手段阻止有丝分裂阻止其他系统中的细胞增殖。因此，C.白念珠菌的有丝分裂进程和形态发生之间的一种新的关系，但控制有丝分裂，相关的极性生长和毒力基因的表达通常在环境信号通路的控制下的机制仍不清楚。 遗传和生物化学筛选结合分子生物学方法和活细胞成像将被用于：1）确定有丝分裂调控因子在C。白念珠菌，以获得对细胞增殖控制的见解;和2）确定有丝分裂，极化生长和毒力基因激活之间的独特关系的机制，以揭示连接这些过程的新电路。我们的工作将有新的意义，细胞增殖，形态发生和毒力的控制在一个重要的病原体，真核细胞周期网络的多样性，以及细胞周期和发展之间的相互作用。

My research focuses on the regulation of eukaryotic cell cycle progression and morphogenesis. Defects in these processes have crucial implications for cell proliferation, development, and cancer. We are specifically investigating the regulation of mitosis and morphogenesis in Candida albicans, an important fungal pathogen of humans. C. albicans can switch between yeast, pseudohyphae, and polarized hyphal cells. This behavior is critical for pathogenesis; cells locked in one form loose virulence. The yeast-to-hyphal switch is regulated by environmental cues, but the mechanisms are not fully understood. Regulation of the cell cycle and cell proliferation in C. albicans is even less clear. Our work on mitotic regulators in C. albicans, including the polo-like kinase Cdc5p, and activators of the Anaphase Promoting Complex/ Cyclosome, revealed distinct features compared to other fungi that suggest re-wiring in the mitotic circuitry. We also demonstrated that cell cycle signals profoundly influence morphogenesis. Mitotic arrest in yeast resulted in highly polarized cells that were distinct from true hyphae in may respects, yet expressed several hyphal virulence genes at later growth stages. In contrast, mitotic arrest through similar means prevents cell proliferation in other systems. Thus, C. albicans shows a novel relationship between mitotic progression and morphogenesis, but the mechanisms controlling mitosis, associated polar growth and expression of virulence genes normally under control of environmental signaling pathways remain unclear. Genetic and biochemical screens coupled with molecular approaches and live cell imaging will be utilized to 1) define the mechanisms of action of mitotic regulators in C. albicans, in order to gain insights on the control of cell proliferation; and 2) determine the mechanisms underlying the distinct relationship between mitosis, polarized growth and activation of virulence genes, in order to uncover novel circuitry linking these processes. Our work will have novel implications for the control of cell proliferation, morphogenesis, and virulence in an important pathogen, the diversity in eukaryotic cell cycle networks, and the interplay between the cell cycle and development.