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

• 批准号: 7338261
• 负责人: Todd B Reynolds
• 金额: $ 6.92万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-05 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338261
• 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

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）：念珠菌物种是50-90％获得免疫缺陷综合征（AIDS）的50-90％的口腔真菌感染的原因。由于引入了高度活跃的抗逆转录病毒疗法（HAART），艾滋病更容易管理。但是，随着HAART年龄治疗的患者人群，老年人免疫缺陷病毒（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。这些患者可能会看到口腔念珠菌感染增加，这些感染疼痛，有时使人衰弱。这种念珠菌感染的最常见原因是白色念珠菌，但是非阿尔比亚人的物种一直是一个日益增长的问题，在某些类型的感染中，几乎发生了很多。例如，从牙齿牙齿口腔炎的艾滋病毒阳性患者中分离出念珠菌的念珠菌几乎与白色念珠菌一样频率（分别为41.3％和48.8％）。 glabrata在口腔干性的患者中受到青睐，这是与老年人经常发现的药物或疾病有关的副作用。假牙，免疫抑制和与HIV阳性阳性人群相关的口腔干燥的结合将越来越有利于已增加的Glabrata感染的频率。针对念珠菌感染，硫唑，多烯和棘齿蛋白的共同用途有三类的抗真菌剂。 C. glabrata是不寻常的，因为它天生对甲唑类抗真菌剂具有更大的抵抗力。另外，已经发现glabrata分离株也对其他类别的药物具有抗性。这些事实凸显了需要识别新的抗真菌剂的必要性。一种新的抗真菌药物的理想候选者将抑制C. glabrata中的蛋白质，这对于在人类宿主中没有密切同源性的生存力至关重要。我们已经确定了一种称为CGOPI1P的蛋白质，该蛋白质是在glabrata中生存所必需的。重要的是，它没有人类同源物，因此它可能是有用的药物靶标。我们打算更好地了解可行性所需的CGOPI1P的机制。 CGOPI1P与酿酒酵母的酵母酵母中的OPI1P蛋白相似。酿酒酵母OPI1P抑制了许多在磷脂生物合成中很重要的基因的表达。磷脂是建造细胞膜所必需的，对生命至关重要。在酿酒酵母中，无需生存能力。我们的假设是，CGOPI1P与酿酒酵母OPI1p一样，抑制了磷脂生物合成基因，但在Glabrata中，由于某些脂质生物合成基因的产生增加，缺乏抑制作用是致命的。我们将通过两个具体目的解决这一假设：1。我们将确定CGOPI1P是否控制磷脂生物合成基因的表达。 2。我们将确定由CGOPI1P调节的基因中的突变是否会抑制细胞的生存力缺损。初步结果表明情况。念珠菌物种在获得的免疫缺陷综合征（AIDS）患者中导致口腔感染。 Glabrata物种是老年人和假牙患者的常见感染来源。它特别抵抗了三种主要类别的抗真菌药剂之一，也发现了对其他主要类别具有抵抗力的分离株，这突出了寻找新类别的抗真菌药物的重要性。