Pheromone Signaling in Pneumocystis Carinii

卡氏肺孢子虫中的信息素信号转导

• 批准号: 7008100
• 负责人: CHARLES FRANCIS THOMAS
• 金额: $ 28.81万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008100
• 关键词: Pneumocystis carinii; Pneumocystis pneumonia; SDS polyacrylamide gel electrophoresis; antibody; autoradiography; biological signal transduction; cell differentiation; cell growth regulation; cell proliferation; chromatin immunoprecipitation; enzyme activity; enzyme substrate; flow cytometry; fungal proteins; hormone receptor; laboratory rat; life cycle; mitogen activated protein kinase; pheromone; phosphorylation; protein purification; protein structure function; proteomics; transcription factor; two dimensional gel electrophoresis

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，可引起艾滋病患者的重症肺炎（PCP）。在肺炎期间，肺孢子虫通过营养型和包囊增殖。调节肺孢子虫生命周期的机制尚不清楚，但信息素诱导的有丝分裂原活化蛋白激酶（MAPK）信号通路调节密切相关真菌中的这一过程。我们的研究表明，卡氏疟原虫MAPK PCM，真菌信息素MAPK的直系同源物，补充酵母中的信息素信号。PCM的表达和活性大大增强营养型相比，包囊，暗示PCM活动在肺孢子虫的生命周期转变。我们已经发现PCM对生化激酶活性具有独特的要求，并且MAPK功能所需的典型磷酸化位点对于PCM激酶活性是不需要的。这些发现提示了PCM的新的调控机制，对PCM的进一步研究可能为病原真菌的信号通路提供新的见解。此外，我们已经确定了推定的信息素受体和转录因子的一部分，这MAPK途径在卡氏肺吸虫。在目前的建议中，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，我们希望能够深入了解卡氏肺孢子虫的生物学特性，为治疗PCP的新药开发提供新的信息。