Regulation of Morphogenesis in C. albicans

描述（由申请人提供）：本提案的长期目标是提供对白色念珠菌发病机制的更好理解。白色念珠菌是最常见的人类真菌病原体，可引起一系列感染，包括免疫功能低下个体的严重全身性疾病。因此，由于新的医疗策略正在增加易感免疫功能低下患者的数量，并且目前的药物对治疗全身性感染不是很有效，因此需要更好地了解真菌发病机制。白色念珠菌毒力的一个主要潜在因素是在出芽和菌丝状态之间切换的能力，这两种状态在产生毒力因子、侵入性生长、在血液中传播和逃避免疫系统的能力上存在差异。由于质膜是活性形态发生的区域，也是抗真菌药物的重要靶点，本课题将重点研究质膜。特别地，具体目标将是确定在我们上一个拨款期间发现的两个质膜隔室的作用。目的1是确定在新生菌丝（胚管）颈部形成边界结构域的因素，并确定其在形态发生中的作用。目的2是确定在菌丝生长的前沿质膜中形成的富含麦角甾醇的结构域的作用。此外，Aim 3将研究通过内吞作用对质膜的重塑如何有助于这些特殊结构域的组织和毒力因子的呈现。这些研究有望通过提供对白色念珠菌发病机制的新见解，以及通过更好地了解当前针对质膜的抗真菌药物（如两性霉素、氟康唑）的机制，帮助开发新的治疗方法。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to provide a better understanding of the mechanisms of Candida albicans pathogenesis. C. albicans is the most common human fungal pathogen and causes a range of infections including severe systemic disease in immunocompromised individuals. A better understanding of the mechanisms of fungal pathogenesis is therefore needed as new medical strategies are increasing the pool of susceptible immunocompromised patients and current drugs are not very effective for treating systemic infections. A major underlying factor for C. albicans virulence is the ability to switch between budding and hyphal states that differ in their ability to produce virulence factors, grow invasively, disseminate in the bloodstream, and evade the immune system. The studies in this proposal will focus on the plasma membrane since it is the zone of active morphogenesis and is also an important target of antifungal drugs. In particular, the Specific Aims will be to determine the role of two plasma membrane compartments that were discovered in our last grant period. Aim 1 is to identify the factors that form a boundary domain at the neck of emerging hyphae (germ tubes) and determine its role in morphogenesis. Aim 2 is to determine the role of an ergosterol-rich domain that forms in the plasma membrane at the leading edge of hyphal growth. In addition, Aim 3 will examine how remodeling of the plasma membrane by endocytosis contributes to the organization of these special domains and to the presentation of virulence factors. These studies are expected to aid in development of novel therapeutic approaches by providing new insight into the mechanisms underlying C. albicans pathogenesis and also by providing a better understanding of the mechanisms of current antifungal drugs that target the plasma membrane (e.g. amphotericin, fluconazole).