BRC-BIO: Polyamine regulated morphogenesis in Candida albicans

在某些真菌中，一个被称为多胺的带正电荷的小分子家族调节从椭圆形酵母样形状到丝状细长细胞类型的转变。这种形状变化与酵母菌的致病性有关，如白色念珠菌，这是本项目的重点。尽管它们在这一过程中发挥着重要作用，但多胺调节真菌生长和形态发生的分子机制仍然是个谜。该项目将使用广泛的研究工具来研究酵母中的多胺如何调节其自身的生产并影响细胞形态发生。所获得的知识将具有基本价值，并有助于确定控制人类和植物致病真菌生长的药物靶标。在主要研究者的直接监督下，大部分工作将由来自代表性不足的背景的本科生和研究生在一个以西班牙裔为主的服务机构进行。参与的学生将获得分子微生物学，遗传学，生物化学和生物信息学方面的宝贵合作和多学科培训。因此，他们将成为进入生物医学领域的竞争对手，扩大STEM劳动力的包容性和多样性。该项目加强了国家科学基金会的使命，即提高教学密集型机构的研究生产力，扩大生物科学中代表性不足群体的参与。在双态真菌中，多胺的细胞生产显着影响其形态从酵母到丝状细胞类型的转变，但介导这种转变的分子机制在很大程度上是未知的。本项目将利用C.白色念珠菌作为模式生物。初步观察证实了酵母形态发生的鸟氨酸脱羧酶和S-腺苷甲硫氨酸脱羧酶活性的必要性;这些酶分别由SPE 1和SPE 2基因编码。反向遗传学的方法将被用来进一步探讨多胺的生物合成和调节在这种酵母。本研究采用多种形态发生分析、代谢谱分析、基因表达分析、蛋白表达分析、基于RNA-Seq的转录谱分析和计算机辅助基因注释等方法，对SPE 1和SPE 2在C.白色念珠菌形态发生和多胺重新生物合成。此外，这项研究将揭示多胺诱导的抑制信号通路，可以利用这些信号通路来确定控制目标，以对抗这种机会性植物和人类真菌病原体引起的感染。总的来说，这项研究将有助于弥合多胺代谢和真菌生理学之间的知识差距。该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

In certain fungi a family of small positively charged molecules called polyamines modulate a transition from oval yeast-like shapes to filamentous elongated cell types. This shape change has been implicated in the pathogenicity of yeasts such as Candida albicans, the focus of this project. Despite the important role they play in this process, the molecular mechanisms by which polyamines regulate fungal growth and morphogenesis remain enigmatic. This project will use a broad range of research tools to investigate how polyamines in yeasts regulate their own production and affect cell morphogenesis. The knowledge gained will be both of fundamental value and helpful in the identification of drug targets to control human and plant disease-causing fungal growth. Under the direct supervision of the Principal Investigator, the majority of the work will be conducted by undergraduate and graduate students from underrepresented backgrounds at a predominantly Hispanic Serving Institution. The participating students will receive invaluable collaborative and multi-disciplinary training in molecular microbiology, genetics, biochemistry, and bioinformatics. They will thereby become competitive for entry into the biomedical field, broadening the inclusivity and diversity in the STEM workforce. This project reinforces the NSF mission to enhance research productivity in teaching-intensive institutions and broaden the participation of underrepresented groups in biological science. In dimorphic fungi the cellular production of polyamines significantly affects their morphological transition from yeast to filamentous cell types, but the molecular mechanisms mediating this transition are largely unknown. This project will investigate the molecular relationship of intracellular polyamine pools and fungal dimorphism using C. albicans as the model organism. The preliminary observations confirmed the necessity of ornithine decarboxylase and S-adenosylmethionine decarboxylase enzyme activities for yeast morphogenesis; these enzymes are encoded by the SPE1 and SPE2 genes, respectively. A reverse genetics approach will be used to further explore polyamine biosynthesis and regulation in this yeast. Using a variety of morphogenetic assays, metabolic profiling, gene expression analysis, protein expression assays, RNA-Seq based transcriptional profiling, and computer-aided gene annotations, this study will characterize the SPE1 and SPE2 coregulatory function in C. albicans morphogenesis and de novo polyamine biosynthesis. Furthermore, this study will uncover the polyamine-induced filamentation signaling pathways that could be harnessed to identify targets of control to combat the infections caused by this opportunistic plant and human fungal pathogen. Overall, this study will contribute to bridge the knowledge gap between polyamine metabolism and fungal physiology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.