N-acetylglucosamine signaling in fungi

描述（由申请人提供）：长期目标是确定营养素如何刺激调节关键细胞功能的信号转导途径。特别是，研究将集中在N-乙酰葡萄糖胺（GlcNAc）。这种氨基糖是GPI锚和蛋白质上N-连接糖基化的关键组分，并且是细胞外聚合物的核心成分，例如人类中的角蛋白或透明质酸以及真菌和寄生虫中的细胞壁几丁质。然而，GlcNAc也激活信号转导途径，在广泛的生物体中诱导深刻的细胞变化。最近的研究表明，GlcNAc信号转导是许多人类疾病的病理基础，包括糖尿病、癌症和神经变性。GlcNAc还刺激人类真菌病原体白色念珠菌以诱导毒力因子的表达，包括从出芽到菌丝生长的转变。因此，C.白色念珠菌和相关酵母将被用作模型系统来定义GlcNAc信号传导的新机制。这些研究将利用最近在C. albicans，这是第一个被克隆的真核GlcNAc转运蛋白。初步研究表明，存在使GlcNAc能够在C.白色念珠菌，但其身份不明。因此，目标1将是确定刺激编码分解GlcNAc所需的GlcNAc分解代谢酶的基因表达的途径。目的2将是确定不同的途径，GlcNAc刺激Ras 1和cAMP途径诱导细胞进行菌丝生长，并打开毒力基因的表达。目的3是鉴定诱导分解代谢和菌丝途径的GlcNAc的细胞内形式。该目的的一部分还将测试细胞调节细胞内GlcNAc合成作为cAMP信号传导的正反馈环的一部分以诱导菌丝生长的假设。在C.白念珠菌和相关酵母将作为理解GlcNAc在其他生物体中如何被感知的重要模型，并将有助于开发用于致病真菌的新治疗方法。 公共卫生相关性：旨在确定糖N-乙酰葡糖胺（GlcNAc）激活细胞信号传导的机制的研究与公共卫生直接相关，因为新出现的数据表明，GlcNAc信号传导是许多流行的人类疾病（如糖尿病，癌症和神经退行性疾病）的病理基础。GlcNAc还刺激人类真菌病原体白色念珠菌以诱导毒力因子。因此，在C.白念珠菌和相关酵母将作为重要的模型，了解如何GlcNAc信号有助于人类疾病，也将有助于发展新的治疗方法的致病真菌。

DESCRIPTION (provided by applicant): The long-term goals are to determine how nutrients stimulate signal transduction pathways that regulate critical cellular functions. In particular, studies will focus on N-acetylglucosamine (GlcNAc). This amino sugar is a key component of GPI anchors and N-linked glycosylation on proteins, and is a core constituent of extracellular polymers, such as keratin or hyaluronan in humans and cell wall chitin in fungi and parasites. However, GlcNAc also activates signal transduction pathways that induce profound cellular changes in a wide range of organisms. Recent studies indicate that GlcNAc signaling underlies the pathology of many human diseases, including diabetes, cancer, and neurodegeneration. GlcNAc also stimulates the human fungal pathogen Candida albicans to induce the expression of virulence factors, including a switch from budding to hyphal growth. Therefore, C. albicans and related yeasts will be used as model systems to define novel mechanisms of GlcNAc signaling. These studies will take advantage of the recent discovery of a plasma membrane GlcNAc transporter (Ngt1) in C. albicans, which is the first eukaryotic GlcNAc transporter to be cloned. Preliminary studies indicate that additional components exist that enable GlcNAc to induce two separate signal pathways in C. albicans, but their identity is not known. Therefore, Aim 1 will be to define the pathway that stimulates the expression of the genes that encode the GlcNAc catabolic enzymes that are needed to break down GlcNAc. Aim 2 will be to identify the distinct pathway by which GlcNAc stimulates Ras1 and the cAMP pathway to induce cells to undergo hyphal growth and to turn on the expression of virulence genes. Aim 3 is to identify the intracellular form(s) of GlcNAc that induce the catabolic and hyphal pathways. Part of this aim will also test the hypothesis that cells modulate intracellular GlcNAc synthesis as part of a positive feedback loop with cAMP signaling in order to induce hyphal growth. Identification of novel mechanisms of GlcNAc signaling in C. albicans and related yeasts will serve as an important model for understanding how GlcNAc is sensed in other organisms, and will aid in the development of novel therapeutic approaches for pathogenic fungi. PUBLIC HEALTH RELEVANCE: Studies aimed at identifying the mechanisms by which the sugar N-acetylglucosamine (GlcNAc) activates cellular signaling are directly relevant to public health, because emerging data indicate that GlcNAc signaling underlies the pathology of many prevalent human diseases, such as diabetes, cancer, and neurodegeneration. GlcNAc also stimulates the human fungal pathogen Candida albicans to induce virulence factors. Therefore, identification of novel GlcNAc signaling mechanisms in C. albicans and related yeasts will serve as important models for understanding how GlcNAc signaling contributes to human diseases and will also aid in the development of novel therapeutic approaches for pathogenic fungi.