Regulatory Mechanisms Controlling Expression of P. gingivalis Surface Structures

控制牙龈卟啉单胞菌表面结构表达的调控机制

• 批准号: 8230810
• 负责人: Mary Ellen Davey
• 金额: $ 28.62万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230810
• 关键词: Adherence; Adult; Affect; Affinity; Anaerobic Bacteria; Antibodies; Architecture; Bacteria; Bacterial Adhesins; Benign; Cardiovascular Diseases; Cell surface; Cells; ChIP-on-chip; Chromatin Loop; Chronic Disease; DNA; DNA Binding; DNA-Binding Proteins; Data; Development; Diabetes Mellitus; Disease; Electrophoretic Mobility Shift Assay; Elements; Environment; Escherichia coli; Exclusion; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Grant; Growth; HU Protein; Histones; Infection; Injury; K antigen; Knowledge; Lead; Link; Measures; Mediating; Membrane; Microarray Analysis; Microbial Biofilms; Nutrient; Operon; Oral; Outcome Study; Parents; Pathogenicity; Pathway interactions; Pattern; Periodontitis; Play; Poison; Polysaccharides; Population; Porphyromonas gingivalis; Production; Prokaryotic Cells; Proliferating; Promoter Regions; Properdin; Protein Family; Proteins; RNA; Regulation; Regulatory Pathway; Relative (related person); Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Signaling Molecule; Spottings; Staging; Stroke; Structure; Surface; Surface Properties; Surveys; System; Systemic disease; Techniques; Testing; Therapeutic Agents; Transcript; Transcriptional Regulation; Vesicle; Virulence; Virulence Factors; Virulent; authority; capsule; cell envelope; chromatin immunoprecipitation; combat; effective therapy; fimbria; genetic regulatory protein; gingipain; member; mutant; novel therapeutics; oral anaerobes; oral biology; oral pathogen; pathogen; prevent; programs; promoter; public health relevance; research study; stem

DESCRIPTION (provided by applicant): Periodontitis is a biofilm-mediated disease that afflicts 35% of the adult population in the US, and persistent infections are associated with systemic disease, including cardiovascular disease and stroke. The proliferation of anaerobic bacteria in the subgingival crevice is central to progression of this chronic disease, with Porphyromonas gingivalis being implicated as one of the primary pathogens. We recently reported that a loss in K-antigen capsule synthesis enhanced biofilm formation in P. gingivalis, hence regulation of this virulence factor plays a key role in pathogenicity and biofilm formation. During preliminary studies, we discovered that a gene with high similarity to the DNA binding protein HU (PG0121) is transcribed with the K- antigen capsule synthesis operon and that this "histone-like" regulatory protein controls expression of the capsule operon. We are now poised to determine the regulatory mechanisms controlling expression of K- antigen capsule. The long-term goal of our research is to elucidate the regulatory mechanisms and signals that control the expression of genes involved in modifying the surface properties of P. gingivalis, and to determine how changes in expression of these genes relate to biofilm development and virulence. The objectives of this application are to characterize the role of HU protein in the synthesis of K-antigen capsule and to investigate the role of the two HU subunits (PG0121 and PG1258) in regulating global gene expression using chromatin immunoprecipitation and microarray analysis. The research proposed in this application is significant because understanding the control of surface property changes is a vital link to understanding the switch this bacterium makes from a quiescent state as a commensal to a virulent pathogen. As an outcome of these studies, we will have established how HU a global regulatory protein controls expression of a key virulence factor, K-antigen capsule. This information will lead to a better understanding of the regulatory networks that either direct P. gingivalis to become a virulent pathogen or to continue to lie low and persist. Our results will potentially lead to the development of new therapeutic strategies for modulating biofilm formation by this oral pathogen. PUBLIC HEALTH RELEVANCE: Periodontal (gum) disease afflicts 35% of the adult population in the US, and persistent infections are associated with systemic diseases, such as diabetes, cardiovascular disease, and stroke. The bacterium Porphyromonas gingivalis is one of the primary oral pathogens associated with severe forms of this disease. The goal of this research is to identify vital mechanisms that control the production of destructive factors by P. gingivalis. These mechanisms are in essence an "Achilles heel" that can be used as a target to stop the injury caused by this bacterium.

描述（由申请人提供）：牙周炎是一种生物膜介导的疾病，困扰着美国 35% 的成年人口，持续感染与全身性疾病有关，包括心血管疾病和中风。龈下缝隙中厌氧菌的增殖是这种慢性疾病进展的核心，牙龈卟啉单胞菌是主要病原体之一。我们最近报道，K 抗原荚膜合成的丧失增强了牙龈卟啉单胞菌生物膜的形成，因此对该毒力因子的调节在致病性和生物膜形成中起着关键作用。在初步研究中，我们发现与DNA结合蛋白HU（PG0121）高度相似的基因与K抗原荚膜合成操纵子一起转录，并且这种“组蛋白样”调节蛋白控制荚膜操纵子的表达。我们现在准备确定控制 K 抗原胶囊表达的调节机制。我们研究的长期目标是阐明控制牙龈卟啉单胞菌表面特性改变的基因表达的调控机制和信号，并确定这些基因表达的变化如何与生物膜发育和毒力相关。本应用的目的是表征 HU 蛋白在 K 抗原荚膜合成中的作用，并使用染色质免疫沉淀和微阵列分析研究两个 HU 亚基（PG0121 和 PG1258）在调节全局基因表达中的作用。本申请中提出的研究具有重要意义，因为了解表面特性变化的控制对于了解这种细菌从共生静止状态向剧毒病原体的转变至关重要。作为这些研究的结果，我们将确定 HU（全局调节蛋白）如何控制关键毒力因子 K 抗原胶囊的表达。这些信息将有助于更好地理解调节网络，这些网络要么引导牙龈卟啉单胞菌成为一种剧毒病原体，要么继续保持低调并持续存在。我们的结果将有可能导致开发新的治疗策略来调节这种口腔病原体的生物膜形成。 公共卫生相关性：牙周（牙龈）疾病困扰着美国 35% 的成年人，持续感染与糖尿病、心血管疾病和中风等全身性疾病有关。牙龈卟啉单胞菌是与这种疾病的严重形式相关的主要口腔病原体之一。本研究的目的是确定控制牙龈卟啉单胞菌产生破坏性因子的重要机制。这些机制本质上是“致命弱点”，可以作为阻止这种细菌造成的损伤的目标。