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Switching and Candida Pathogenesis-A Molecular Analysis

转换和念珠菌发病机制 - 分子分析

基本信息

批准号：
6901948
负责人：
DAVID R. SOLL
金额：
$ 25.73万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-06-01 至 2007-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6901948
关键词：
Candida albicans acetylation candidiasis disease /disorder model fungal genetics gel mobility shift assay gene expression gene mutation gene targeting genetic promoter element genetic transcription laboratory mouse molecular cloning phenotype transcription factor virulence

项目摘要

DESCRIPTION (Verbatim from Applicant's Abstract): Candida albicans switches spontaneously, reversibly and at high frequency between a limited number of general phenotypes distinguishable by colony morphology. Switching is highly pleiotropic, regulating a variety of phenotypic characteristics and involving the differential expression of phase-specific genes. Switching therefore, provides colonizing populations with spontaneous variants for rapid adaptation during commensalism and pathogenesis. Using the white-opaque phase transition in strain WO-1 as an experimental system, we have demonstrated that the histone deacetylase Hda1p functions as a suppressor of switching in the white-to-opaque direction, that the silent information regulatory Sir2p is not involved in the white-opaque transition, but functions as a suppressor of a second switching system analogous to that in strain 3153A, and that phase specific genes are regulated downstream of the switch event through phase-specific trans-acting factors. We now propose 1) to develop a more accurate model of the downstream regulatory circuitry involved in phase specific gene expression, 2) to elucidate the protein-DNA and protein-protein interactions involved in the regulation of select white and opaque phase genes, with emphasis on the role of the MADS box proteins in opaque phase expression of OP4, Rbf1p in white phase expression of WH11 and transcription of the phase regulated trans-acting factor EFG1, 3) to elucidate the roles of acetylation/deacetylation and gene silencing in switching, and 4) to assess the impact of the deletion of phase-specific regulatory molecules on pathogenesis in two animal models, one in which white phase cells are more pathogenic than opaque phase cells, and the other in which opaque phase cells are more pathogenic than white phase cells. The first three aims have been formulated so that they provide several independent starting points for a reverse genetic approach for elucidating switch loci and the switching mechanism.

描述（申请人摘要中的逐字描述）：白色念珠菌开关自发地、可逆地和在有限数量的可通过菌落形态学区分的一般表型。切换高度多效性，调节多种表型特征，阶段特异性基因的差异表达。因此切换，为殖民群体提供了快速适应的自发变体发病过程中的作用。利用白色-不透明的相变在WO-1菌株作为实验系统中，我们已经证明，去乙酰化酶Hda 1 p的功能是抑制白色到不透明的转换，方向，沉默的信息监管Sir 2 p不参与白色-不透明转变，但用作第二次转换的抑制剂系统类似于菌株3153 A中系统，且相特异性基因被通过特定于相位的反作用，因素我们现在建议1）开发一个更准确的下游模型，参与时相特异性基因表达的调节回路，2）阐明蛋白质-DNA和蛋白质-蛋白质的相互作用，选择白色和不透明相基因的调节，重点是 MADS盒蛋白在不透明相中表达OP 4，Rbf 1 p在白色相中表达 WH 11的表达和相位调节反式作用因子的转录 EFG 1，3）阐明乙酰化/去乙酰化和基因沉默的作用 4）评估删除特定阶段的影响，调节分子对两种动物模型中发病机制的影响，其中一种模型中有白色相细胞比不透明相细胞致病性更强，而另一种中，不透明期细胞比白色期细胞致病性更强。前三已经制定了目标，以便他们提供几个独立的开始，点的反向遗传方法，以阐明开关基因座和切换机制