Determining Genetic and Molecular Mechanisms that Specify C. albicans Morphology

确定白色念珠菌形态的遗传和分子机制

• 批准号: 7931920
• 负责人: Patricia Lynn Carlisle
• 金额: $ 2.83万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-03 至 2012-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931920
• 关键词: Antifungal Agents; Antifungal Therapy; Candida albicans; Candidiasis; Cells; Characteristics; Cytolysis; Data; Development; Disease; Drug Design; Drug resistance; Environment; Filament; Gene Expression; Gene Expression Profile; Genes; Genetic Determinism; Goals; Growth; HIV; Hyphae; Immune system; Individual; Infection; Invaded; Knowledge; Lead; Medical; Microarray Analysis; Molecular; Molecular Genetics; Morphology; Mouth Diseases; Mycoses; Oral candidiasis; Pathway interactions; Patients; Phagocytosis; Play; Population; Predisposing Factor; Property; Quality of life; Recording of previous events; Regulation; Research; Risk; Role; Saccharomycetales; Specific qualifier value; Symptoms; Testing; The science of Mycology; Tissues; Virulence; Virulence Factors; Work; Yeasts; base; design; dosage; fungus; improved; macrophage; mouse model; mutant; neutrophil; novel; oral cavity epithelium; oral fungal; pathogen; public health relevance; research study; resistant strain; transcription factor

DESCRIPTION (provided by applicant): Candida albicans is the main etiologic agent of oral candidiasis. Individuals most at risk for developing this mucosal infection are those with compromised immune systems or people with other predisposing factors. Symptoms of oral candidiasis can be severe, leading to a poor quality of life for these patients. Drug resistant strains of C. albicans are also emerging, making this oral fungal pathogen even more difficult to treat. One of the essential virulence properties that allows C. albicans to cause disease is its ability to reversibly switch morphology from budding yeast cells to pseudohyphal and hyphal filaments. The long term goal of our research is to gain a better understanding of the C. albicans virulence property, morphological switching, in order to develop new antifungal therapies to treat oral fungal infections. Currently, it is thought that the pseudohyphal and hyphal morphologies are determined by distinetgene sets, however direct evidence is lacking. The molecular mechanisms that control hyphal growth are not well defined. We have now generated a strain that allows us to explore these questions. Recently, our lab identified a novel filament-specific transcriptional regulator, Ume6, which is important for hyphal extension and filament-specific gene expression. We found that when UME6 is expressed at high constitutive levels, C. albicans grows as a nearly complete hyphal population. During an infection, we observed that high-level constitutive UME6 expression is sufficient to promote virulence. Interestingly, we observed that lower levels of UME6 expression resulted in a majority pseudohyphal population. We found that UME6 levels differentially regulated the expression of several known filament-specific genes. Our hypothesis is that UME6 levels determine C. albicans morphology in a dosage-dependent manner by up-regulating overlapping subset of filament-specific genes, including genes required for proper hyphal formation. In order to test this hypothesis, we will carry out experiments designed to accomplish the following aims: 1) determine the gene expression profile of C. albicans growing as pseudohyphal and hyphal morphologies specified by UME6 expression levels, 2) determine the role of UME6 in the regulation of the molecular mechanisms that specify proper hyphal growth. Public Health Relevance: At the completion of our studies, we expect to have a more in-depth knowledge of C. albicans morphological switching, which may lead to the development of more effective antifungal therapies to treat oral disease. Candida albicans causes severe oral disease, leading to a poor quality of life. The proposed study will increase our understanding of a property that is essential to the ability of C. albicans to cause disease.

描述(申请人提供)：白色念珠菌是口腔念珠菌病的主要病原体。患这种粘膜感染的风险最大的人是那些免疫系统受损的人或有其他易感因素的人。口腔念珠菌病的症状可能很严重，导致这些患者的生活质量较差。白色念珠菌的抗药性菌株也在出现，这使得这种口腔真菌病原体更加难以治疗。白念珠菌致病的基本毒力特性之一是它能够可逆地将形态从萌芽的酵母细胞切换到假菌丝和菌丝。我们研究的长期目标是更好地了解白色念珠菌的毒力特性、形态转换，以便开发治疗口腔真菌感染的新的抗真菌药物。目前认为假菌丝和菌丝形态是由差异基因组决定的，但缺乏直接证据。控制菌丝生长的分子机制还不是很清楚。我们现在已经产生了一种允许我们探索这些问题的压力。最近，我们的实验室发现了一种新的细丝特异转录调控因子Ume6，它对菌丝伸长和细丝特异基因表达具有重要作用。我们发现，当UME6在高组成水平表达时，白色念珠菌几乎作为一个完整的菌丝群体生长。在感染期间，我们观察到高水平的结构性UME6表达足以促进毒力。有趣的是，我们观察到较低水平的UME6表达导致了大多数假菌丝种群。我们发现，UME6水平对几个已知的细丝特异基因的表达有不同的调节作用。我们的假设是，UME6水平通过上调细丝特异基因的重叠子集，包括正常菌丝形成所需的基因，以一种剂量依赖的方式决定白色念珠菌的形态。为了验证这一假说，我们将开展旨在实现以下目的的实验：1)确定由UME6表达水平指定的假菌丝和菌丝形态的白念珠菌的基因表达谱；2)确定UME6在调节指定适当菌丝生长的分子机制中的作用。 公共卫生相关性：在我们的研究完成后，我们希望对白色念珠菌的形态转换有更深入的了解，这可能会导致开发更有效的抗真菌疗法来治疗口腔疾病。白色念珠菌会引起严重的口腔疾病，导致生活质量下降。这项拟议的研究将增加我们对一种对白色念珠菌致病能力至关重要的特性的理解。