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: 8963710
• 负责人: Mary Ellen Davey
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963710
• 关键词: Adult; Anaerobic Bacteria; Antisense RNA; Bacteria; Biochemical; Cardiovascular Diseases; Cell surface; Cells; ChIP-seq; Chromosomes; Chronic; Communities; DNA; Development; Diabetes Mellitus; Disease; Disease Progression; Disease model; EMSA; Elements; Etiology; Family member; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Goals; Homeostasis; Immune; Inflammatory; Integrins; Interferometry; K antigen; Knock-out; Knowledge; Lead; Link; Lipopolysaccharides; Metabolism; Microbe; Microbial Biofilms; Modeling; Molecular; Mus; Nucleotides; Nutritional; Outcome Study; Pathogenesis; Pathogenicity; Periodontal Diseases; Play; Polysaccharides; Population; Porphyromonas gingivalis; Prevention; Production; Proteins; RNA; Regulation; Regulatory Pathway; Research; Role; Stroke; Structure; Surface; Surface Properties; Systemic disease; Techniques; Testing; Transcript; United States; Virulence; Virulent; Work; capsule; cost; immunoregulation; member; mouse model; mutant; novel therapeutics; oral anaerobes; oral pathogen; pathogen; programs; public health relevance; response; subgingival biofilm; transcriptome sequencing

 DESCRIPTION (provided by applicant): Porphyromonas gingivalis (Pg) is a Gram-negative anaerobe, strongly implicated in the etiology of adult periodontal disease. This research will increase our understanding of the molecular mechanisms that control synthesis of Pg cell surface glycans, and determine how changes in synthesis relate to biofilm persistence and pathogenicity. Our overarching model is that the biofilm state acts as a reservoir of bacteria, while capsule synthesis is linked to a transition to virulence and disruption of homeostasis. We have discovered that DNABII family members in Pg (HU PG0121 and HU PG1258) are involved in controlling synthesis of this surface polysaccharide. DNABII proteins are members of the Nucleoid Associated Proteins (NAPs), a class of proteins that possess multiple functions in maintaining the structure and function of DNA and RNA and are known to be critical for regulation of cell metabolism, the response to environmental perturbations, and in controlling the transition to and from a quiescent state. We have also identified an antisense RNA encoded in the 5'-end of the capsule locus (PG0104-PG0121) within a large 77bp inverted repeat (77bpIR) element. Deletion or over- expression of the region encoding this asRNA alters the synthesis of both LPS and K-antigen capsule. Our working model is that DNABII proteins interact with this asRNA and control expression of both the sense and antisense transcripts in this region. We have designated the asRNA asSuGR, for antisense Surface Glycan Regulator. The central hypothesis of this project is that HU PG0121 and HU PG1258 are key NAPs that play a fundamental role in modulating Pg pathogenicity. In these studies we will determine how these proteins and the 77bpIR element control synthesis of capsule and LPS. Our overall goal is to identify regulatory pathways that control the switch from a persistent, surface-attached state as a commensal to a virulent state capable of disrupting microbe-host homeostasis. 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 commensal makes to a virulent pathogen. As an outcome of these studies, we will have characterized regulatory mechanisms that control the synthesis of surface glycans, key virulence determinants. 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.

 描述（由适用提供）：牙龈卟啉单胞菌（PG）是一种革兰氏阴性的厌食症，与成人牙周疾病的病因强有关。这项研究将增加我们对控制PG细胞表面糖的合成的分子机制的理解，并确定合成的变化与生物膜持久性和致病性的关系如何相关。我们的总体模型是，生物膜状态充当细菌的储层，而胶囊合成与向病毒的过渡和破坏稳态有关。我们发现，PG（HU PG0121和HU PG1258）中的DNABII家族成员参与控制这种表面多糖的合成。 DNABII蛋白是核苷相关蛋白（NAPS）的成员，这是一类蛋白质，在维持DNA和RNA的结构和功能方面潜在多种功能，并且已知对于调节细胞代谢的调节，对环境扰动的反应以及对Quiescent Centent and quiescent State的过渡而言至关重要。我们还确定了在胶囊基因座（PG0104-PG0121）的5'末端中编码的反义RNA，在大型77bp倒置重复（77BPIR）元素中。编码该ASRNA的区域的删除或过表达改变了LPS和K-Antigen胶囊的合成。我们的工作模型是，DNABII蛋白与该区域中感觉和反义转录本的这种asrna相互作用。我们已将Asrna Assugr指定为反义表面聚糖调节剂。该项目的中心假设是HU PG0121和HU PG1258是关键的小睡，在调节PG致病性方面起着基本作用。在这些研究中，我们将确定这些蛋白质以及77BPIR元件控制胶囊和LP的合成。我们的总体目标是确定控制从持续的，表面连接状态的转变，作为能够破坏微生物 - 宿主体内稳态的强大状态的共同状态。本应用程序中提出的研究很重要，因为了解对表面特性变化的控制是了解这种共同病原体所产生的转换的至关重要的联系。作为这些研究的结果，我们将表征控制表面聚糖合成的调节机制，关键病毒确定。这些信息将使人们更好地理解监管网络，这些法规网络要么指导牙龈疟原虫成为一种有毒的病原体，要么继续持续下来并持续存在。我们的结果将有可能领导 开发通过这种口腔病原体调节生物膜形成的新治疗策略。