Pheromone Signaling in Pneumocystis Carinii

卡氏肺孢子虫中的信息素信号转导

• 批准号: 7382470
• 负责人: CHARLES FRANCIS THOMAS
• 金额: $ 27.44万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382470
• 关键词: Acquired Immunodeficiency Syndrome; Adrenal Cortex Hormones; Autoradiography; Binding; Binding Sites; Biochemical; Biology; Cell Cycle; Chimeric Proteins; Complement; Condition; Count; Cyst; Databases; Epithelium; Figs - dietary; Gel; Gene Expression; Genes; Infection; Investigation; Life Cycle Stages; Ligands; Lung; MEKs; Mass Spectrum Analysis; Mating Types; Mitogen-Activated Protein Kinases; Organism; Orthologous Gene; Pathogenicity; Pathway interactions; Patients; Pheromone; Pheromone Receptors; Phosphorylation; Phosphorylation Site; Phosphotransferases; Pneumocystis; Pneumocystis carinii; Pneumocystis carinii Pneumonia; Pneumonia; Population; Procedures; Process; Proliferating; Promoter Regions; Protein Analysis; Proteins; Proteomics; Radioactive; Reaction; Receptor Signaling; Recombinants; Regulation; Reporter Genes; Research Personnel; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Role; Saccharomyces cerevisiae; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; Sorting - Cell Movement; Specificity; System; Threonine; Time; Tyrosine; Yeasts; analog; chromatin immunoprecipitation; concept; drug development; fungus; insight; light microscopy; mutant; novel; pathogen; programs; receptor; receptor function; transcription factor; upstream kinase

DESCRIPTION (provided by applicant): Pneumocystis is an opportunistic fungal pathogen which causes severe pneumonia (PCP) in patients with AIDS. During pneumonia, Pneumocystis proliferates through trophic forms and cysts. Mechanisms regulating the Pneumocystis life cycle are not well defined, however a pheromone-induced mitogen-activated protein kinase (MAPK) signaling pathway regulates this process in closely-related fungi. Our studies demonstrate that the P. carinii MAPK PCM, an ortholog to fungal pheromone MAPKs, complements pheromone signaling in yeast. PCM expression and activity are greatly augmented in trophic forms compared to cysts, implicating PCM activity in Pneumocystis life cycle transition. We have discovered that PCM has unique requirements for biochemical kinase activity, and the typical phosphorylation sites required for MAPK function are not needed for PCM kinase activity. These findings suggest novel regulation of PCM, the further study of which might provide insights into signaling pathways hi pathogenic fungi. Additionally, we have identified putative pheromone receptors and a transcription factor as part of this MAPK pathway in P. carinii. In the current proposal, we hypothesize that the pheromone-induced mitogen-activated protein kinase (MAPK) pathway regulates cellular differentiation and proliferation of P. carinii. We will investigate these concepts through three independent but interrelated Specific Aims. Through these investigations we hope to gain insights into P. carinii biology which may provide new information for novel drug development to treat PCP.

描述(申请人提供)：肺孢子虫是一种机会性真菌病原体，可导致艾滋病患者的重症肺炎(PCP)。在肺炎期间，肺孢子虫通过营养形式和包囊增殖。调控肺孢子虫生命周期的机制尚不清楚，但信息素诱导的丝裂原活化蛋白激酶(MAPK)信号通路在密切相关的真菌中调节这一过程。我们的研究表明，P.carinii MAPK PCM是真菌信息素MAPKs的同源基因，它补充了酵母中的信息素信号。与包囊相比，PCM在营养型中的表达和活性显著增强，这意味着PCM在肺孢子虫生命周期的转变中具有活性。我们发现PCM对生化激酶活性有独特的要求，而MAPK功能所需的典型磷酸化位点不是PCM激酶活性所必需的。这些发现提示了对PCM的新的调控，对其的进一步研究可能会为病原真菌的信号通路提供见解。此外，我们已经在卡氏肺孢子虫中鉴定出可能的信息素受体和转录因子是该MAPK途径的一部分。在目前的方案中，我们假设信息素诱导的丝裂原活化蛋白激酶(MAPK)途径调节卡氏肺孢子虫的细胞分化和增殖。我们将通过三个独立但相互关联的具体目标来研究这些概念。通过这些研究，我们希望对卡氏肺孢子虫的生物学有更深入的了解，从而为治疗PCP的新药开发提供新的信息。