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RNA interference in the fungal pathogen Candida albicans

真菌病原体白色念珠菌中的 RNA 干扰

基本信息

批准号：
6822636
负责人：
JANET F STAAB
金额：
$ 17.3万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2006-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6822636
关键词：
Candida albicans RNA interference candidiasis gene induction /repression genetic regulation heterochromatin molecular cloning open reading frames virulence virus genetics virus morphology

项目摘要

DESCRIPTION (provided by applicant): Candida albicans is the most common etiologic agent of oropharyngeal candidiasis (OPC), an opportunistic infection in HIV v patients occurring in as many as 90% of AIDS patients at some point during the course of HIV disease. OPC is also seen at an appreciable rate in head and neck cancer patients due to impaired salivary function resulting from radiation therapy. A salient characteristic of C. albicans is the ability to grow in different morphological forms, from ovoid yeasts to filamentous hyphae. The expression of several virulence factors is intimately associated with morphology, and strains impaired in morphological transitions have reduced virulence in animal models. The molecular mechanism of how C. albicans coordinates expression of virulence genes with morphological forms is unclear. The recently described phenomenon of gene silencing termed post-transcriptional gene silencing (PTGS) triggered by double-stranded RNA (dsRNA) appears to be a conserved mechanism involved in resistance to viruses, protection of the genome from repetitive elements, developmental timing, and heterochromatin silencing. The PTGS effect is achieved by the degradation of mRNA termed RNA interference (RNAi). Genetic studies across many species have identified several homologous genes involved in RNAi, and in every organism where a PTGS function has been described, a member of the Argonaute protein family has been found. The finding of an ARGONAUTE gene homolog in C. albicans suggests that the fungus is capable of PTGS. This novel gene regulatory system may prove to be important in C. albicans for the regulation of virulence genes indirectly by affecting morphological transitions. The goals of this exploratory/developmental proposal are: (1) to uncover evidence in C. albicans of gene regulation by PTGS through RNAi; and (2) to determine the role of PTGS in control of virulence attributes through morphological transitions, and in maintenance of centromeric heterochromatic structure. The proposed initial studies will take genetic and molecular approaches to determine the capability of C. albicans to perform PTGS through analyses of RNAi constructs and gene knock out strains. Although the role of RNAi in the biology of C. albicans is unknown, the probability is high that novel gene regulatory mechanisms will be found that are common to other fungal pathogens.

描述（由申请人提供）：白色念珠菌是口咽念珠菌病（OPC）最常见的病原体，OPC是HIV v患者的机会性感染，在HIV疾病过程中的某个时间点，多达90%的AIDS患者发生。由于放射治疗导致的唾液功能受损，OPC在头颈癌患者中也以可观的比率出现。C.白色念珠菌是以不同形态形式生长的能力，从卵形酵母到丝状菌丝。几种毒力因子的表达与形态密切相关，在动物模型中，形态转变受损的菌株毒力降低。探讨了C.白念珠菌毒力基因的表达与形态的协调性尚不清楚。最近描述的由双链RNA（dsRNA）触发的称为转录后基因沉默（PTGS）的基因沉默现象似乎是涉及抗病毒、保护基因组免受重复元件、发育定时和异染色质沉默的保守机制。PTGS效应通过称为RNA干扰（RNAi）的mRNA降解来实现。对许多物种的遗传学研究已经鉴定了几个参与RNAi的同源基因，并且在已经描述了PTGS功能的每种生物中，都发现了Argonaute蛋白家族的成员。白色念珠菌表明真菌能够PTGS。这种新的基因调控系统可能在C.白念珠菌的毒力基因的调节间接影响形态转变。这个探索性/发展性的建议的目标是：（1）发现证据，在C。白念珠菌的基因调控PTGS通过RNAi;（2）确定PTGS的作用，通过控制毒力属性的形态转变，并在维护着丝粒异染色质结构。初步研究将采用遗传学和分子生物学方法来确定C.通过分析RNAi构建体和基因敲除菌株来进行PTGS。虽然RNAi在C.由于白色念珠菌尚不清楚，因此发现其他真菌病原体常见的新型基因调节机制的可能性很高。