Determining Genetic and Molecular Mechanisms that Specify C. albicans Morphology

描述（由申请人提供）：白色念珠菌是口腔念珠菌病的主要病原体。最有可能发生这种粘膜感染的人是免疫系统受损的人或有其他诱发因素的人。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很差。耐药菌株C.白色念珠菌也在出现，使得这种口腔真菌病原体更加难以治疗。白色念珠菌引起疾病的原因是其能够可逆地将形态从芽殖酵母细胞转变为假菌丝和菌丝丝。我们的长期研究目标是更好地了解C。白念珠菌的毒力特性、形态学转换，以开发新的抗真菌疗法来治疗口腔真菌感染。目前认为假菌丝和菌丝形态是由不同基因组决定的，但缺乏直接证据。控制菌丝生长的分子机制还没有很好的定义。我们现在已经产生了一种菌株，使我们能够探索这些问题。最近，我们的实验室发现了一个新的有害生物特异性转录调控因子，Ume6，这是重要的菌丝延伸和有害生物特异性基因表达。我们发现当UME 6在高组成型水平表达时，C.白色念珠菌以几乎完全的菌丝群体生长。在感染过程中，我们观察到高水平的组成型UME6表达足以促进毒力。有趣的是，我们观察到较低水平的UME 6表达导致大多数假菌丝群体。我们发现，UME6水平差异调节几个已知的肿瘤特异性基因的表达。我们的假设是，UME6水平决定C。白念珠菌形态的剂量依赖性的方式通过上调重叠子集的病原体特异性基因，包括基因所需的适当的菌丝形成。为了验证这一假设，我们将进行旨在实现以下目标的实验：1）确定C。白念珠菌生长为假菌丝和由UME6表达水平指定的菌丝形态，2）确定UME6在指定适当菌丝生长的分子机制的调节中的作用。 公共卫生相关性：在我们的研究完成后，我们希望有一个更深入的了解C。白色念珠菌形态转换，这可能导致更有效的抗真菌疗法治疗口腔疾病的发展。白色念珠菌引起严重的口腔疾病，导致生活质量差。这项研究将增加我们对一个性质的理解，这个性质对C。白色念珠菌导致疾病。

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.