Regulation of Candida albicans Pathogenesis by the Signaling Mucin Msb2

信号粘蛋白 Msb2 对白色念珠菌发病机制的调节

基本信息

批准号：
8458676
负责人：
PAUL James CULLEN
金额：
$ 38.17万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-13 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8458676
关键词：
Adhesions Affect Antibiotic Resistance Architecture Aspartic Endopeptidases Behavior Binding Binding Proteins Candida Candida albicans Cell Surface Proteins Cell Wall Cell membrane Cell surface Cells Complex Cues Dependence Development Drug Targeting Environment Extracellular Domain Face Filament Gene Targeting Germination Glucans Goals Growth Guanosine Triphosphate Phosphohydrolases Health Homologous Protein Human Immune system Immunocompromised Host In Vitro Infection Mannans Mannose Measures Mediating Membrane Membrane Glycoproteins Membrane Proteins Microbe Microbial Biofilms Mitogen-Activated Protein Kinases Modeling Mucins Mus Oral Oral candidiasis Pathogenesis Pathway interactions Peptide Hydrolases Play Process Protein Family Proteins Regulation Relative (related person)Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Signal Transduction Signal Transduction Pathway Streptococcus gordonii Surface Testing Virulence beta-Glucans combat dectin 1 environmental stressor extracellular histatin 5 histidine-rich proteins inhibitor/antagonist member microbial mouse dectin-2 mouse model mutant oropharyngeal thrush pathogen programs public health relevance quorum sensing receptor response sensor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The goal of this study is to identify proteins and mechanisms that regulate filamentous growth and pathogenesis in the oral microbe Candida albicans, the primary pathogen causing oral candidiasis. One of the major regulators of filamentous growth in Candida and other fungal species are signal transduction pathways. The signaling pathway on which the proposal is focused is the Cek1 MAPK pathway, which plays a critical role in hyphal invasive growth. We will investigate the cell-surface signaling mucin Msb2 that regulates this pathway to determine how Msb2 is activated in C. albicans, what proteins regulate Msb2 function, what Msb2 is sensing at the cell surface, and what roles it might play in regulating filamentous growth, biofilm formation, and immune system interactions. We will test quorum-sensing molecules and expression of Sap proteases for Msb2-dependent Cek1 activation. We will also test whether the extracellular glycodomain of Msb2, which we show is released from cells, plays a role in biofilm/mat formation and cell-surface architecture. Signaling mucins such as Msb2 are an evolutionary conserved class of cell-surface glycoproteins that have only recently been studied in microbial species. Signaling pathways sense changes in the extracellular environment and relay those changes to the inside of the cell. Because signaling pathways exert global control over cellular behaviors, they represent attractive targets to shut down or inhibit cellular differentiation programs or target genes. Given the serious threat of this fungal pathogen to human health, and given that current strategies to treat Candidal infections are in many cases ineffectual, our long-term goal is a deeper understanding of the pathogenic response in this microbe in order to identify a new class of drug targets.

描述（由申请人提供）：这项研究的目的是鉴定调节口服微生物念珠菌的丝状生长和发病机理的蛋白质和机制，该白色念珠菌是导致口腔念珠菌病的主要病原体。念珠菌和其他真菌物种丝状生长的主要调节因子之一是信号转导途径。该提案集中的信号通路是CEK1 MAPK途径，该途径在菌丝浸润性生长中起着关键作用。我们将研究调节该途径的细胞表面信号粘蛋白MSB2，以确定白色念珠菌中MSB2的激活，哪些蛋白质调节MSB2功能，MSB2在细胞表面上感应的是什么以及它在调节丝状生长，生物膜形成，生物膜形成以及免疫系统相互作用中可能起的作用。我们将测试群体感应分子和SAP蛋白酶的表达，以依赖MSB2依赖性CEK1激活。我们还将测试MSB2的细胞外糖结域是否从细胞中释放出来，在生物膜/MAT形成和细胞表面结构中起作用。信号粘蛋白（例如MSB2）是一种进化保守的细胞表面糖蛋白，直到最近才在微生物物种中进行了研究。信号通路感知细胞外环境的变化，并将这些变化转移到细胞内部。由于信号通路对细胞行为产生全球控制，因此它们代表了关闭或抑制细胞分化程序或靶基因的有吸引力的目标。考虑到这一点的严重威胁真菌对人类健康的病原体，并且鉴于当前治疗候选感染的策略在许多情况下是无效的，我们的长期目标是对该微生物中的致病反应有更深入的了解，以识别一类新的药物靶标。