Transcription Factor Targets of Cdk8 Dependent Signaling in C. albicans

 描述（由申请方提供）：真菌白色念珠菌既是一种重要的人类健康负担，也是一种用于研究形态转变调控的新兴模型系统。C.新生儿、女性生殖道和口腔-食管道中的白色念珠菌粘膜感染引起慢性发病。C.白色念珠菌还可在受损患者中引起播散性念珠菌病，死亡率在30- 50%之间，并且据报道这些感染是医院感染的第二大常见死因（在美国每年约10，000例死亡）。C.白色念珠菌最适合在人体内生长，并且可以在一系列环境条件下在不同的细胞形态之间转变。这些形态学变化赋予生物体促进其毒力的特性，并受不同环境信号的影响，涉及多个转录调节因子。我们的工作，以及其他人的工作，使用遗传突变体表明，介体，DNA结合激活剂和所有真核生物中的一般转录机制之间的中介，在控制这些转换中起着重要作用。一个新兴的非经典的观点是，介体如何参与调节重要的生理转变，以响应环境线索是它的直接调节转录因子，通过 其激酶活性。在这个建议中，我们将确定激酶活性的机制， 梭白念珠菌Cdk 8调节驱动与形态和毒力相关的变化的转录因子。我们还将确定是否环境信号调节Cdk 8激酶活性。最近的数据也表明C.白色念珠菌Cdk 8对于鼠模型中的毒力是重要的。拟议的研究将使我们能够完全模拟复杂的真菌病原体信号通路是如何调节的。此外，由于转录因子本身是众所周知的不良药物靶点，了解Cdk 8如何调节这些转录因子的作用将有助于表征以前未开发的调节C的潜在药物靶点。体内白色念珠菌。由于人类Cdk 8抑制剂已被证明具有很大的潜力，作为治疗设计，以减轻化疗耐药性，重要的是要了解这些化合物对C。白色念珠菌，免疫功能低下人群中的潜在病原体。

 DESCRIPTION (provided by applicant): The fungus Candida albicans is both a significant human health burden and an emerging model system for the study of the regulation of morphological transitions. C. albicans mucosal infections in neonates, in the female reproductive tract, and in the oral- esophageal tract cause chronic morbidity. C. albicans can also cause disseminated candidiasis in compromised patients with mortality rates between 30-50%, and these infections have been reported to be the second most common cause of death from nosocomial infections (~10,000 deaths per year in the U.S.). C. albicans is optimized for growth in humans and can transition between different cellular morphologies under a range of environmental conditions. These morphological changes confer properties to the organism that facilitate its virulence, and are influenced by different environmental signals and involve multipl transcriptional regulators. Our work, and the work of others, using genetic mutants shows that Mediator, an intermediary between DNA-bound activators and the general transcription machinery in all eukaryotes, plays a major role in controlling these transitions. An emerging non-canonical view of how Mediator participates in the regulation of important physiological transitions in response to environmental cues is its direct regulation of transcription factors via its kinase activity. In this proposal, we will determine the mechanism by which the kinase activity of C. albicans Cdk8 regulates transcription factors that drive changes associated with morphology and virulence. We will also determine whether environmental signals regulate the Cdk8 kinase activity. Recent data also show that C. albicans Cdk8 is important for virulence in a murine model. The proposed research will enable our ability to fully model how complex fungal pathogen signaling pathways are regulated. In addition, since transcription factors themselves are notoriously poor drug targets, understanding how Cdk8 regulates the action of these transcription factors will help characterize a previously untapped target for potential drugs that modulate C. albicans in vivo. Because inhibitors of human Cdk8 have been shown to have great potential as therapies designed to mitigate chemotherapy resistance, it is important to understand the impact of these compounds on C. albicans, a potential pathogen in immunocompromised populations.