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N-acetylglucosamine signaling in fungi

真菌中的 N-乙酰氨基葡萄糖信号传导

基本信息

批准号：
8240116
负责人：
James B Konopka
金额：
$ 30.47万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8240116
关键词：
Acetylglucosamine Amino Sugars Biochemical Biological Models Candida Candida albicans Catabolism Cell Nucleus Cell Wall Cell membrane Cell physiology Cells Chemicals Chitin Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Diabetes Mellitus Diploidy Enzymes Eukaryotic Cell Feedback Gene Expression Gene Proteins Genes Goals Growth Haploidy Homologous Gene Human Hyaluronan Hyphae Insertional Mutagenesis Keratin Link Malignant Neoplasms Mammalian Cell Mediating Metabolism Modeling Morphogenesis Nerve Degeneration Nutrient Organism Parasites Pathogenesis Pathology Pathway interactions Phosphorylation Polymers Proteins Public Health Relative (related person)Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Staging Study Section Testing Virulence Virulence Factors Yarrowia lipolytica Yeasts analog cell type extracellular fungus glycosylation human disease insight microbial mutant novel novel therapeutic intervention pathogen public health relevance response sugar

项目摘要

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.

描述(由申请人提供)：长期目标是确定营养物质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-乙酰氨基葡萄糖(GlcNAc)。这种氨基糖是蛋白质上GPI锚点和N-连接糖基化的关键成分，也是细胞外聚合物的核心成分，例如人类的角蛋白或透明质酸，真菌和寄生虫的细胞壁几丁质。然而，GlcNAc也激活了信号转导通路，在广泛的生物体中引发了深刻的细胞变化。最近的研究表明，GlcNAc信号是许多人类疾病的基础，包括糖尿病、癌症和神经退行性变。GlcNAc还刺激人类真菌病原体白色念珠菌诱导毒力因子的表达，包括从萌芽到菌丝生长的切换。因此，白念珠菌和相关酵母菌将被用作模型系统来定义GlcNAc信号的新机制。这些研究将利用最近在白色念珠菌中发现的质膜GlcNAc转运蛋白(Ngt1)，这是第一个克隆的真核GlcNAc转运蛋白。初步研究表明，GlcNAc还存在能够在白色念珠菌中诱导两条不同的信号通路的额外成分，但它们的身份尚不清楚。因此，目标1将是定义刺激编码GlcNAc分解代谢酶的基因表达的途径，这些酶是分解GlcNAc所需的。目的2确定GlcNAc刺激Ras1和cAMP途径以诱导细胞进行菌丝生长和开启毒力基因表达的不同途径。目的3是确定诱导分解代谢和菌丝途径的细胞内形式(S)的GlcNAc。这一目标的一部分也将检验这样的假设，即细胞调节细胞内GlcNAc的合成，作为与cAMP信号的正反馈循环的一部分，以诱导菌丝生长。白念珠菌及其相关酵母菌中GlcNAc信号新机制的发现，将为了解GlcNAc如何在其他生物中被感知提供一个重要的模型，并将有助于开发新的致病真菌治疗方法。与公共健康相关：旨在确定糖N-乙酰氨基葡萄糖(GlcNAc)激活细胞信号的机制的研究与公共健康直接相关，因为新出现的数据表明，GlcNAc信号是许多流行的人类疾病，如糖尿病、癌症和神经退化的病理基础。GlcNAc还刺激人类真菌病原体白色念珠菌诱导毒力因子。因此，在白色念珠菌和相关酵母中识别新的GlcNAc信号机制将成为了解GlcNAc信号如何在人类疾病中发挥作用的重要模型，也将有助于开发新的致病真菌治疗方法。