Pheromone Signaling in Pneumocystis Carinii

描述(申请人提供)：卡氏肺孢子虫是一种机会主义者 致残障患者重症肺炎的真菌病原体 免疫力如艾滋病患者。卡氏肺吸虫生活史较差 明白了。在与卡氏肺孢子虫相关的真菌中，营养缺乏和 脱水是信息素交配因子释放的主要刺激因素 激活有丝分裂原激活的蛋白激酶(MAPK)，导致有丝分裂 细胞周期停滞、接合和减数分裂，并增强致病性。MAPK 是信息素诱导的信号转导级联反应中的重要分子 它控制着这些事件。作为一种调节生物体的基本分子 在生命周期中，MAPK活性受到高度调控。双重磷酸化是 需要激活，可变的MAPK活性和表达是 仅限于某些生命周期形式。我们的初步研究表明，P. Carinii具有一种与真菌信息素诱导密切相关的MAPK MAPK。我们假设信息素诱导的有丝分裂原激活蛋白 激酶(MAPK)信号转导通路调节细胞分化 以及卡氏肺孢子虫生物体的增殖。作为一个必不可少的组件， 真菌的生活史，对卡氏假单胞菌MAPK的研究将导致 增强了对卡氏肺孢子虫生活史、致病性和导致 治疗卡氏肺孢子虫肺炎的新型治疗药物的开发。至 为了评估这些假设，我们将进行几项平行的调查。 不同生命周期形式的MAPK活性和表达将被访问 确定卡氏肺孢子虫MAPK是否对P.carinii MAPK进行差异调控。 脊椎动物的生命周期。我们将鉴定和鉴定卡氏肺孢子虫信息素 受体和卡氏肺吸虫交配型的分离。我们将访问是否 营养缺乏、缺氧或温度变化会导致有丝分裂细胞 周期停滞导致减数分裂和包囊的形成，以及 MAPK级联的抑制剂可阻断这些作用。我们还将调查是否 孤立的交配型经历单倍体有丝分裂，或者如果交配型的混合是 对减数分裂和包囊的形成是必不可少的。通过这些调查， 我们希望获得对生命周期调节和 致病性OFP。卡里尼。

DESCRIPTION (provided by applicant): Pneumocystis carinii is an opportunistic fungal pathogen which causes severe pneumonia in patients with impaired immunity such as patients with AIDS. The life cycle of P. carinii is poorly understood. In fungi related to P. carinii, nutrient deprivation and dessication are the major stimuli for the release of pheromone mating factors which activate a mitogen-activated protein kinase (MAPK), resulting in mitotic cell cycle arrest, conjugation and meiosis, and increased pathogenicity. MAPK is the essential molecule in the pheromone-induced signal transduction cascade which controls these events. As an essential molecule regulating an organism's life cycle, MAPK activity is highly regulated. Dual phosphorylations are requiring for activation, and variable MAPK activity and expression are restricted to certain life cycle forms. Our initial studies indicate that P. carinii possesses a MAPK which is closely related to fungal pheromone-induced MAPKs. We hypothesize that the pheromone-induced mitogen-activated protein kinase (MAPK) signal transduction cascade regulates cellular differentiation and proliferation of P. carinii organisms. As an essential component in the life cycle of fungi, investigation of the P. carinii MAPK will result in an enhanced understanding of the P. carinii life cycle, pathogenicity, and lead to development of novel therapeutic agents to treat P. carinii pneumonia. To evaluate these hypotheses, we will undertake several parallel investigations. MAPK activity and expression in separated life cycle forms will be accessed to determine whether P. carinii MAPK is differentially regulated over the P. carinii life cycle. We will identify and characterize the P. carinii pheromone receptors and separate P. carinii mating types by FACS. We will access whether nutrient deprivation, hypoxia, or temperature changes results in mitotic cell cycle arrest leading to meiosis and formation of the cyst, and whether inhibitors of the MAPK cascade block these effects. We will also investigate if isolated mating types undergo haploid mitosis or if mixing of mating types is essential for meiosis and formation of the cyst. Through these investigations, we hope to gain important insights into the life cycle regulation and pathogenicity ofP. carinii.