Role of the OPI1 gene in controlling viability of Candida glabrata

描述（由申请人提供）：念珠菌属是50-90%获得性免疫缺陷综合征（AIDS）患者口腔真菌感染的原因。由于采用了高效抗逆转录病毒疗法（HAART），艾滋病更容易控制。然而，随着接受HAART治疗的患者年龄的增长，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的增加，这是痛苦的，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，然而非白色念珠菌物种已经成为一个日益严重的问题，并且在某些类型的感染中几乎经常发生。例如，从HIV阳性的义齿性口炎患者中分离出光滑念珠菌的频率几乎与分离出念珠菌的频率相同。白色念珠菌分别占41.3%和48.8%。C. glabrata在口干患者中更受欢迎，口干是与药物或老年人常见的疾病相关的副作用。假牙、免疫抑制和与老龄化的HIV阳性人群相关的口干的组合将越来越有利于已经上升的C。glabrata感染有三种类型的抗真菌药通常用于治疗念珠菌感染，唑类，多烯类和棘白菌素类。C. glabrata是不寻常的，因为它天生对唑类抗真菌剂更具抗性。此外，C.已发现光滑分离物也对其它种类的药物具有抗性。这些事实突出了需要确定新的抗真菌剂。一种新的抗真菌药物的理想候选者将抑制C. glabrata是生存力所必需的，在人类宿主中没有相似的同源物。我们已经确定了一种名为CgOpi 1 p的蛋白质，它是C.光滑的重要的是，它没有人类同源物，因此它可能是一个有用的药物靶标。我们打算更好地了解CgOpi 1 p的生存机制。CgOpi 1 p类似于面包酵母酿酒酵母中的Opi 1 p蛋白。S.酿酒酵母Opi 1 p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，是生命所必需的。In S.酿酒酵母Opi 1 p不是生存力所必需的。我们假设CgOpi 1 p和S.酿酒酵母Opi 1 p抑制磷脂生物合成基因，但在C. glabrata，缺乏抑制是致命的，由于增加生产的一些脂质生物合成基因。我们将通过两个具体目标来解决这个假设：1。我们将确定CgOpi 1 p是否控制磷脂生物合成基因的表达。2.我们将确定CgOpi 1 p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。念珠菌属引起50-90%的获得性免疫缺陷综合征（AIDS）患者的口腔感染。种C.光滑是老年人和假牙患者的常见感染源。它对三大类抗真菌剂之一的唑类抗真菌剂特别耐药，并且已经发现分离株对其他主要类别也具有耐药性，这突出了发现新类别抗真菌剂的重要性。

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.