Pheromone Signaling in Pneumocystis Carinii

卡氏肺孢子虫中的信息素信号转导

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：肺孢子虫是一种机会性真菌病原体，可导致艾滋病患者出现严重肺炎（PCP）。在肺炎期间，肺孢子虫通过营养形式和包囊进行增殖。肺孢子虫生命周期的调节机制尚不明确，但信息素诱导的丝裂原激活蛋白激酶 (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（真菌信息素 MAPK 的直系同源物）可补充酵母中的信息素信号传导。与包囊相比，营养形式的 PCM 表达和活性大大增强，这表明 PCM 活性在肺孢子虫生命周期转变中。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对于PCM激酶活性来说并不需要。这些发现表明了 PCM 的新调控，对其的进一步研究可能会为致病真菌的信号通路提供见解。此外，我们还鉴定了假定的信息素受体和转录因子作为 P. carinii 中 MAPK 途径的一部分。在当前的提议中，我们假设信息素诱导的丝裂原激活蛋白激酶（MAPK）途径调节卡氏疟原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，我们希望深入了解卡氏疟原虫生物学，这可能为治疗 PCP 的新药开发提供新信息。