权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Phosphate and Inositol Pyrophosphate Metabolism in Candida albicans

白色念珠菌中的磷酸盐和肌醇焦磷酸代谢

基本信息

批准号：
10580205
负责人：
RONDA J ROLFES
金额：
$ 45.88万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580205
关键词：
Address Affect Affinity Animals Antifungal Agents Attenuated Bacteria Binding Biological Assay Biology Candida Candida albicans Carbon Cell Nucleus Cells Cues Cyclic AMP Cyclic AMP-Dependent Protein Kinases Development Diphosphates Drug Targeting Environment Enzymes Eukaryota Family Filament Gastrointestinal tract structure Gene Expression Genes Growth Guanosine Triphosphate Phosphohydrolases Heat Stress Disorders High Pressure Liquid Chromatography Homeostasis Human Human body Hyphae Immunocompromised Host Individual Infection Inorganic Phosphate Transporter Inositol Invertebrates Knowledge Life Link Liquid substance Measures Metabolism Microbial Biofilms Modeling Morphogenesis Morphology Mucous Membrane Mutate Mutation Mycoses Nitrogen Nutrient Oral cavity Oxidative Stress Induction Pathogenicity Pathway interactions Persons Phospho-Specific Antibodies Phosphoric Monoester Hydrolases Phosphorus Phosphorylation Phosphotransferases Plants Polymers Polyphosphates Proliferating Proteins Radiolabeled Regulation Research Ring Finger Domain Route Saccharomyces cerevisiae Side Signal Pathway Signal Transduction Signaling Molecule Sirolimus Skin Tissue Solid Structure System Systemic infection Tertiary Protein Structure Testing Vacuole Virulence Virulent Western Blotting Work Yeasts biological adaptation to stress cytotoxic detection of nutrient inorganic phosphate mortality mutant myoinositol novel pathogenic fungus polymerization response trait transcription factor ubiquitin ligase uptake urogenital tract

项目摘要

Candida albicans is an opportunistic fungal pathogen and a major cause of human fungal infections. It resides as a commensal on the skin and mucosal tissues (oral cavity, gastrointestinal tract and urogenital tract) of the human body in most healthy individuals. However, it is responsible for causing superficial mucosal infections and life-threatening systemic infections, particularly in the immunocompromised. Upwards of 400,000 people are infected annually worldwide with life-threatening infections, and mortality rates ranging between 47-75%, in spite of anti-fungal treatments. We found that Candida infections respond to phosphate limitation by becoming filamentous and virulent. Filamentation consists of the formation of hyphae, morphological structures that aid the yeast cell in scavenging for nutrients. In C. albicans, the filamentous form is necessary for virulence. Phosphate metabolism and homeostasis is critical for the survival of all cells from bacteria and yeast to plants and animals. Opportunistic fungal pathogens must acquire phosphate from the human host, and this uptake is essential for virulence. On the other side, too much phosphate is cytotoxic, and cells maintain mechanisms for phosphate homeostasis (the PHO pathway). Homeostasis involves phosphate scavengers, inorganic phosphate (Pi) transporters, polymerization of Pi into polyphosphate, and storage of polyphosphate in the vacuole. Expression of the genes that encodes these proteins is increased when Pi becomes limiting. Phosphate limitation also affects a second pathway, the Target-of-Rapamycin (TOR) pathway, that links nutrient abundance to proliferation. The TOR pathway increases the expression of pro-growth genes when nutrients are abundant, and stress-response genes when nutrients are limiting. The TOR pathway regulates the morphogenesis pathways in fungal pathogens. Recent evidence suggests that inositol pyrophosphates regulate the PHO and TOR pathways to affect both phosphate homeostasis and proliferation. Inositol pyrophosphates are high-energy carrying, intracellular signaling molecules found in all eukaryotes. The intersection between phosphate homeostasis, proliferation, morphogenesis and inositol pyrophosphates is understudied in Candida albicans. I propose to combine my lab’s expertise in inositol pyrophosphate metabolism with our expertise in C. albicans pathobiology to address the following hypothesis: Inositol pyrophosphates regulate phosphate homeostasis and TOR signaling in response to phosphate limitation in Candida albicans to affect morphology and virulence.

白色念珠菌是一种机会性真菌病原体，也是人类真菌的主要原因感染。它以共生体的形式存在于皮肤和粘膜组织(口腔、胃肠道在大多数健康人身上)。然而，它是负责引起浅表粘膜感染和危及生命的全身感染，尤其是在免疫功能受损的人群中。每年有超过40万人被感染全世界都有危及生命的感染，死亡率在47%-75%之间，尽管抗真菌治疗。我们发现念珠菌感染对磷酸盐限制的反应是变得丝状的和有毒的。丝状化包括菌丝的形成，帮助酵母细胞寻找营养的形态结构。在白色念珠菌中，丝状形态是致病力所必需的。磷酸盐代谢和动态平衡对所有细菌细胞的生存至关重要酵母菌传播给动植物。机会性真菌病原体必须从人类宿主，而这种摄取对于致病力是必不可少的。另一方面，过多的磷酸盐是细胞毒性的，细胞维持磷酸盐稳态的机制(pho途径)。动态平衡包括磷酸盐清除剂，无机磷(PI)转运体，将PI聚合成聚磷酸盐，并将聚磷酸盐储存在液泡中。表达式当等电点变得有限时，编码这些蛋白质的基因的比例就会增加。磷酸盐限制也影响第二个途径，雷帕霉素靶点(TOR)途径，连接营养丰富到增殖。TOR途径增加促生长因子的表达营养丰富时的基因，营养有限时的应激反应基因。这个 Tor途径调控真菌病原菌的形态发生途径。最近的证据表明，肌醇焦磷酸调节PHO和TOR 影响磷酸盐动态平衡和增殖的途径。焦磷酸肌醇是高能携带的细胞内信号分子，存在于所有真核生物中。交叉口在磷酸盐的动态平衡、增殖、形态发生和肌醇焦磷酸盐之间在白色念珠菌中未被研究。我建议将我的实验室在肌醇方面的专业知识焦磷酸盐代谢与我们在白念珠菌病理生物学方面的专业知识，以解决以下问题假说：肌醇焦磷酸调节磷酸盐稳态和TOR信号转导白色念珠菌对磷酸盐限制的反应影响形态和毒力。