Role of the OPI1 gene in controlling viability of Candida glabrata

OPI1 基因在控制光滑念珠菌活力中的作用

基本信息

批准号：
7433731
负责人：
Todd B Reynolds
金额：
$ 6.76万
依托单位：
UNIVERSITY OF TENNESSEE KNOXVILLE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-05 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7433731
关键词：
Acquired Immunodeficiency Syndrome Address Adverse effects Age Aging Anabolism Antifungal Agents Azole resistance Azoles Candida Candida albicans Candida glabrata Cell Survival Cell membrane Class Condition Defect Denture Stomatitis Dentures Drug Delivery Systems Elderly Essential Genes Facility Construction Funding Category Frequencies Gene Expression Gene Proteins Gene Targeting Genes Genetic Screening Goals HIV Highly Active Antiretroviral Therapy Homologous Gene Human Immunologic Deficiency Syndromes Immunosuppression Infection Inositol Laboratories Life Lipids Mutation Mycoses Numbers Oral candidiasis Pain Patients Pharmaceutical Preparations Phenotype Phospholipids Play Polyenes Population Production Protein Overexpression Proteins Regulon Repression Resistance Role Saccharomyces Saccharomyces cerevisiae Source Staging Testing Therapeutic immunosuppression Transcription Repressor/Corepressor Transcriptional Regulation Virulence Xerostomia acquired immunodeficiency fungus immune function older patient oral fungal oral infection pathogen promoter

项目摘要

DESCRIPTION (provided by applicant): Candida species are the cause oral fungal infections in 50-90% of patients that have Acquired Immune Deficiency Syndrome (AIDS). AIDS is more manageable due to the introduction of Highly Active Antiretroviral Therapy (HAART). However, as the population of patients treated by HAART ages, the needs of elderly Human Immunodeficiency Virus (HIV) positive patients will become a very important concern because immune function will decline. These patients may see an increase in oral Candida infections, which are painful and sometimes debilitating. The most common cause of such Candida infections is Candida albicans, however non-albicans species have been a growing problem, and in some types of infections occur nearly as often. For example, Candida glabrata was isolated from HIV positive patients with denture stomatitis nearly as often as C. albicans (41.3% and 48.8%, respectively). C. glabrata is favored in patients with dryness of mouth, which is a side effect associated with medications or conditions frequently found in the elderly. The combination of dentures, immunosuppression, and dryness of mouth associated with an aging HIV positive population will increasingly favor the already rising frequency of C. glabrata infections. There are three classes of antifungals in common use against Candida infections, the azoles, the polyenes, and the echinocandins. C. glabrata is unusual in that it is innately more resistant to the azole class of antifungals. In addition, C. glabrata isolates have been found that are resistant to the other classes of drugs as well. These facts highlight the need to identify new antifungal agents. The ideal candidate for a new antifungal drug will inhibit a protein in C. glabrata that is essential for viability that does not have a close homolog in the human host. We have identified a protein called CgOpi1p that is required for viability in C. glabrata. Importantly, it has no human homologs, thus it could be a useful drug target. We intend to better understand the mechanism(s) by which CgOpi1p is required for viability. CgOpi1p is similar to the Opi1p protein in the bakers' yeast Saccharomyces cerevisiae. S. cerevisiae Opi1p represses the expression of a number of genes that are important in phospholipid biosynthesis. Phospholipids are required for construction of the cell's membrane, and are essential for life. In S. cerevisiae Opi1p is not required for viability. Our hypothesis is that CgOpi1p, like S. cerevisiae Opi1p, represses phospholipid biosynthetic genes, but in C. glabrata, a lack of repression is lethal due to increased production of some lipid biosynthetic gene. We will address this hypothesis by two specific aims: 1. We will determine if CgOpi1p controls expression of phospholipid biosynthetic genes. 2. We will determine if mutations in genes regulated by CgOpi1p will suppress the cell's viability defect. Preliminary results suggest that this is the case. Candida species cause oral infections in 50-90% of Acquired Immunodeficiency Syndrome (AIDS) patients. The species C. glabrata is a common source of infection in the elderly and patients with dentures. It is particularly resistant to one of the three major classes of antifungal agents called the azoles, and isolates have been discovered that are resistant to the other main classes as well, which highlights the importance of finding new classes of antifungal agents.

描述（由申请人提供）： 50-90% 的获得性免疫缺陷综合症 (AIDS) 患者的口腔真菌感染是由念珠菌引起的。由于高效抗逆转录病毒疗法（HAART）的引入，艾滋病变得更容易控制。然而，随着HAART治疗患者群体的老龄化，老年人类免疫缺陷病毒（HIV）阳性患者的需求将成为一个非常重要的问题，因为免疫功能会下降。这些患者可能会发现口腔念珠菌感染增加，这会带来痛苦，有时甚至使人衰弱。此类念珠菌感染的最常见原因是白色念珠菌，但非白色念珠菌物种已成为一个日益严重的问题，并且在某些类型的感染中几乎同样频繁发生。例如，从患有假牙口腔炎的 HIV 阳性患者中分离出光滑念珠菌的频率几乎与白色念珠菌一样高（分别为 41.3% 和 48.8%）。光滑念珠菌最受口干患者的青睐，口干是与药物或老年人常见病症相关的副作用。与艾滋病毒阳性人群老龄化相关的假牙、免疫抑制和口干等因素的结合将越来越有利于已经不断上升的光滑念珠菌感染频率。常用来对抗念珠菌感染的抗真菌药物有三类：唑类、多烯类和棘白菌素类。光滑念珠菌的不同寻常之处在于它天生对唑类抗真菌药具有更强的抵抗力。此外，已发现光滑念珠菌分离株也对其他类别的药物具有抗药性。这些事实凸显了识别新抗真菌剂的必要性。新抗真菌药物的理想候选药物将抑制光滑念珠菌中的一种蛋白质，该蛋白质对于生存至关重要，但在人类宿主中没有密切的同源物。我们已经鉴定出一种名为 CgOpi1p 的蛋白质，它是 C. glabrata 生存所需的。重要的是，它没有人类同源物，因此它可能是一个有用的药物靶点。我们打算更好地了解 CgOpi1p 生存所需的机制。 CgOpi1p 与面包酵母酿酒酵母中的 Opi1p 蛋白相似。酿酒酵母 Opi1p 抑制许多在磷脂生物合成中重要的基因的表达。磷脂是构建细胞膜所必需的，并且对于生命至关重要。在酿酒酵母中，Opi1p 并不是生存所必需的。我们的假设是，CgOpi1p 与酿酒酵母 Opi1p 一样，抑制磷脂生物合成基因，但在光滑 C. glabrata 中，由于某些脂质生物合成基因的产量增加，缺乏抑制是致命的。我们将通过两个具体目标来解决这一假设： 1. 我们将确定 CgOpi1p 是否控制磷脂生物合成基因的表达。 2. 我们将确定受CgOpi1p 调控的基因突变是否会抑制细胞的活力缺陷。初步结果表明情况确实如此。 50-90% 的获得性免疫缺陷综合症 (AIDS) 患者由念珠菌引起口腔感染。光滑念珠菌是老年人和戴假牙患者的常见感染源。它对三大类抗真菌药物之一（唑类）特别具有抗药性，并且已发现分离株对其他主要抗真菌药物也具有抗药性，这凸显了寻找新抗真菌药物类别的重要性。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Candida albicans uses multiple mechanisms to acquire the essential metabolite inositol during infection.

白色念珠菌在感染过程中使用多种机制来获取必需的代谢物肌醇。

DOI：
发表时间：
2008-06
期刊：
影响因子：
3.1
作者：
Chen, Ying;Kauffman, Sarah;Reynolds, Todd B
通讯作者：
Reynolds, Todd B

The inositol regulon controls viability in Candida glabrata.

肌醇调节子控制光滑念珠菌的活力。

DOI：
发表时间：
2010-02
期刊：
影响因子：
0
作者：
Bethea, Emily K;Carver, Billy J;Montedonico, Anthony E;Reynolds, Todd B
通讯作者：
Reynolds, Todd B

Candida albicans OPI1 regulates filamentous growth and virulence in vaginal infections, but not inositol biosynthesis.

白色念珠菌 OPI1 调节阴道感染中的丝状生长和毒力，但不调节肌醇生物合成。

DOI：
发表时间：
2015
期刊：
影响因子：
3.7
作者：
Chen, Ying;de Bernardis, Flavia;Yu, Shang;Sandini, Silvia;Kauffman, Sarah;Tams, Robert N;Bethea, Emily;Reynolds, Todd B
通讯作者：
Reynolds, Todd B

Strategies for acquiring the phospholipid metabolite inositol in pathogenic bacteria, fungi and protozoa: making it and taking it.

获取病原菌、真菌和原生动物中磷脂代谢物肌醇的策略：制造并服用它。