Structure and Expression of Pneumocystis Antigen Genes

肺孢子虫抗原基因的结构和表达

• 批准号: 7384436
• 负责人: JAMES Richard STRINGER
• 金额: $ 32.13万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7384436
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Antigenic Variation; Antigens; Behavior; Biology; Complementarity Determining Regions; Data; Development; Drug Formulations; Evolution; Family; Frequencies; Future; Gene Conversion; Gene Family; Generations; Genes; Genetic Recombination; Genetic Transcription; Genomics; Goals; Host Defense; Human; Hypoxanthine Phosphoribosyltransferase; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Individual; Infection; Ligand Binding; Ligands; Modeling; Mus; Numbers; Parasites; Patients; Pneumocystis; Pneumocystis carinii; Pneumocystis carinii Pneumonia; Problem Solving; Process; Proliferating; Protein Region; Proteins; Rattus; Receptors, Antigen, B-Cell; Research; Rodent; Site; Sodium Glutamate; Staging; Structure; Study models; Surface; Surface Antigens; T-Lymphocyte; Testing; Therapeutic; Variant; Work; design; fungus; improved; latent infection; member; mouse model; receptor; tool

DESCRIPTION (provided by applicant): Pneumocystis pneumonia is a serious problem for AIDS patients and other immunocompromised individuals. This illness is caused by an unusual fungus (Pneumocystis jirovecii) that proliferates little when outside of a human being. Therefore, studies on the biology of Pneumocystis have relied principally upon P. carinii and P. murina, which inhabit rats and mice, respectively. Human Pneumocystis has at least one gene family (MSG) that has been implicated in antigenic variation in studies on P. carinii and P. murina. In this application, we propose structural and functional studies on gene families (MSG, PRT, MSR) in rodent Pneumocystis species. The overall goal of these studies is to determine if Pneumocystis gene families function to allow members of this genus to parasitize an immunocompetent host. Aim 1 will employ genomic data from P. carinii to determine where the proteins encoded by a gene family vary, and how this variability evolved. Deducing the mode of evolution will allow us to infer general function. Aim 2 will use genomic information to investigate expression of the P. carinii MSG family, a process that entails recombination at a unique expression site to cause a change in the sequence of the expressed gene. The bulk of the evidence suggests that gene conversion creates variation in the expressed copy of MSG. Aim 2 will examine this and other possibilities. Aim 3 will determine how often recombination occurs at the DCS locus of P. murina. These studies will both establish mice as a model for studying antigen variation in Pneumocystis, and set the stage for studies described in Aim 4, which will test the idea that the adaptive immune response can influence the degree of variation in MSG gene sequences residing at the expression site.

描述（由申请人提供）：肺孢子菌肺炎对于艾滋病患者和其他免疫功能低下的个体来说是一个严重的问题。这种疾病是由一种不寻常的真菌（耶氏肺孢子虫）引起的，这种真菌在体外几乎不繁殖。因此，对肺孢子虫生物学的研究主要依赖于分别栖息于大鼠和小鼠的卡氏肺孢子虫和鼠肺孢子虫。在卡氏肺孢子虫和鼠肺孢子虫研究中，人类肺孢子虫至少有一个基因家族 (MSG) 与抗原变异有关。在此应用中，我们提出了对啮齿类肺孢子虫物种基因家族（MSG、PRT、MSR）的结构和功能研究。这些研究的总体目标是确定肺孢子虫基因家族的功能是否允许该属的成员寄生于具有免疫能力的宿主。目标 1 将利用来自 P. carinii 的基因组数据来确定基因家族编码的蛋白质在何处发生变化，以及这种变异是如何进化的。推论进化模式将使我们能够推断出一般功能。目标 2 将使用基因组信息来研究 P. carinii MSG 家族的表达，该过程需要在独特的表达位点进行重组，从而导致表达基因的序列发生变化。大量证据表明，基因转换会导致味精表达副本的变异。目标 2 将检验这种可能性和其他可能性。目标 3 将确定 P. murina 的 DCS 基因座发生重组的频率。这些研究将建立小鼠作为研究肺孢子虫抗原变异的模型，并为目标 4 中描述的研究奠定基础，该研究将检验适应性免疫反应可以影响位于表达位点的 MSG 基因序列变异程度的想法。