Regulation of morphogenesis in C. albicans

白色念珠菌形态发生的调节

• 批准号: 8301082
• 负责人: James B Konopka
• 金额: $ 38.78万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301082
• 关键词: Affect; Amphotericin; Antifungal Agents; Biological Assay; Candida albicans; Caspofungin; Cell Wall; Cell membrane; Cells; Copper; Defect; Development; Diagnostic Procedure; Drug effect disorder; Effectiveness; Endocytosis; Environment; Fluconazole; Genes; Goals; Growth; Histology; Human; Individual; Integral Membrane Protein; MCC protein; Mediating; Medical; Membrane; Membrane Microdomains; Membrane Proteins; Morphogenesis; Mus; Mutation; Organ; Orthologous Gene; Pathogenesis; Peripheral; Phagosomes; Pharmaceutical Preparations; Phenotype; Phosphorylation; Process; Property; Protein Kinase; Proteins; Regulation; Resistance; Resolution; Role; Saccharomyces cerevisiae; Side; Sphingolipids; Stress; Structure; Systemic infection; Testing; Therapeutic; Therapeutic Intervention; Transmembrane Domain; Virulence; Virulence Factors; aging population; base; drug sensitivity; extracellular; improved; macrophage; meetings; mutant; novel; novel therapeutic intervention; oxidation; paralogous gene; pathogen; success

DESCRIPTION (provided by applicant): Lethal systemic infections caused by Candida albicans, the most common human fungal pathogen, are on the rise as new medical treatments and an aging population are increasing the pool of susceptible individuals. There is an urgent need to improve the therapeutic management of this escalating problem since current diagnostic procedures and antifungal drugs have limited effectiveness. The pathogenic effects of C. albicans are caused by its ability to grow in the host and disseminate to internal organs. Central to these processes is the plasma membrane. This essential barrier mediates secretion of virulence factors, morphogenesis, cell wall synthesis, and interfaces with the extracellular environment. The importance of the plasma membrane for virulence is underscored by the fact that it is directly or indirectly the target of the most effective antifungal drugs. Recent studies revealed that fungal plasma membranes are composed of discrete subdomains whose function in virulence and drug action is not known. Therefore, the Specific Aims are focused on the newly discovered plasma membrane subdomains called MCC/eisosomes. They consist of integral membrane proteins (MCC portion) and adjacent peripheral membrane proteins (eisosome). These unique domains are distinct from lipid rafts in that they are stable 300 nm-sized punctate patches that are associated with membrane invaginations. Our hypothesis is that MCC/eisosomes are essential for proper plasma membrane function and that their analysis will provide new paradigms for plasma membrane organization and the mechanisms of pathogenesis. In support of this, preliminary studies demonstrate that the MCC protein Sur7 is broadly important for morphogenesis, cell wall integrity, invasive growth, and virulence. Another key phenotype is that sur7¿ cells are >1,000-fold sensitive to copper, which correlates with decreased growth in macrophage phagosomes that are enriched in copper. The major goals are to identify the important proteins in these domains (Aim 1), to determine how the assembly and disassembly of MCC/eisosomes is regulated and can be perturbed by drugs (Aim 2), and to define the roles of MCC/eisosomes in virulence (Aim 3). The results are expected to aid development of new therapeutic approaches by identifying novel plasma membrane functions in fungal pathogenesis. Furthermore, these results will increase our understanding of current antifungal drugs and improve the prospects for more effective use. PUBLIC HEALTH RELEVANCE: New medical treatments and an aging population are increasing the pool of individuals that are susceptible to lethal systemic infections caused by Candida albicans, the most common human fungal pathogen. Improved therapeutic approaches are needed to meet this escalating problem due to the limitations of current antifungal drugs. The proposed studies on the C. albicans plasma membrane, the essential barrier that surrounds the cell, are expected to improve therapeutic success by providing a better understanding of current antifungal drugs and by identifying new targets for therapeutic intervention.

描述（由适用提供）：随着新医疗治疗和老龄化人群的增加，由白色念珠菌引起的致命全身感染正在上升。由于当前的诊断程序和抗真菌药物的有效性有限，因此迫切需要改善此不断升级问题的治疗管理。白色念珠菌的致病作用是由于其在宿主中生长并传播到内部器官的能力引起的。这些过程的核心是质膜。这种基本障碍介导了病毒因子的分泌，形态发生，细胞壁合成以及与细胞外环境的界面。质膜对病毒的重要性被直接或间接是最有效的抗真菌药物的靶标而造成的。最近的研究 表明真菌质膜由不知道病毒和药物作用功能的离散亚域组成。因此，具体目的集中于称为MCC/EIISOSOMES的新发现的质膜子域。它们由整体膜蛋白（MCC部分）和相邻的外周膜蛋白（EIISOSOMOS）组成。这些独特的域与脂质筏不同，因为它们是稳定的300 nm尺寸。与膜起伏相关的点状斑块。我们的假设是，MCC/Eisosomes对于适当的质膜功能至关重要，它们的分析将为质膜组织和发病机理提供新的范式。为此，初步研究表明，MCC蛋白SUR7对于形态发生，细胞壁完整性，侵入性生长和病毒至关重要。另一个关键表型是SUR7¿细胞对铜敏感> 1,000倍，这与富含铜的巨噬细胞吞噬体的生长降低有关。主要目标是确定这些结构域中的重要蛋白质（AIM 1），以确定如何调节MCC/EIISOSOMES的组装和拆卸，并可能受到药物的扰动（AIM 2），并定义MCC/EIISOSOMES在病毒中的作用（AIM 3）。预计该结果将通过鉴定新型质膜功能在真菌发病机理中的新治疗方法的开发。此外，这些结果将提高我们对当前抗真菌药物的理解，并改善前景，以更有效。 公共卫生相关性：新的医疗治疗和老龄化的人群正在增加容易受到念珠菌念珠菌（最常见的人类真菌病原体）致死性全身感染的个人。由于当前的抗真菌药物的局限性，需要改进的治疗方法来解决这一不断升级的问题。对白色念珠菌质膜的拟议研究（围绕细胞的基本障碍）预计将通过更好地理解当前的抗真菌药物并确定治疗性干预的新靶标，这将改善治疗成功。