Studies on the virulence regulation in Porphyromonas

卟啉单胞菌毒力调控的研究

基本信息

批准号：
9888964
负责人：
Hansel M. Fletcher
金额：
$ 39.42万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888964
关键词：
Acetylation Acetyltransferase Address Affect Amino Acids Anaerobic Bacteria Bacteria Biological Models Cardiovascular Diseases Complex Data Development Disease Elements Enzyme Precursors Enzymes Etiology Funding Gene Expression Genes Genetic Genetic Transcription Goals Gram-Negative Anaerobic Bacteria Growth Health Homeostasis Homologous Gene Human Inflammatory Laboratories Lead Light Link Membrane Proteins Molecular Operon Oxidative Stress Parents Pathogenicity Pathology Pathway interactions Periodontal Diseases Periodontal Pocket Phase Phenotype Pigments Porphyromonas Porphyromonas gingivalis Post-Translational Protein Processing Prevention Protein Sortings Proteins Regulation Research Resistance Rheumatoid Arthritis Role Site Site-Directed Mutagenesis Sorting - Cell Movement Structure System Systemic disease Testing Virulence Virulence Factors base comparative design disorder prevention gene product gingipain member microbial host mutant novel novel therapeutic intervention novel therapeutics oral pathogen pathogen programs public health relevance success

项目摘要

DESCRIPTION (provided by applicant): Porphyromonas gingivalis, a black-pigmented, Gram-negative anaerobe, is an important etiological agent of periodontal disease and is also linked to cardiovascular disease, rheumatoid arthritis and other systemic diseases. The recent designation of P. gingivalis as a "keystone pathogen" further highlights its ability to adapt to th harsh inflammatory conditions of the periodontal pocket and disrupt host-microbial homeostasis, which is partly responsible for the pathology observed in periodontal disease. Thus, to survive and orchestrate the microbial/host activities that can lead to disease, suggest that P. gingivalis possesses a complex regulatory network probably involving transcriptional and post-transcriptional mechanisms. While a key element in modulating the pathogenic potential of P. gingivalis is the post- translational modification of several of the major surface proteins/structures, there is a gap in our understanding of the components and mechanism(s) of this circuitry. The specific hypothesis to be addressed in this application is that via acetylation the novel vimA (virulence modulating) gene product is involved in the post-translational control of several major surface proteins in P. gingivalis including gingipain maturation/activation. This hypothesis is based on the observations made in the previous funding period where we have characterized the bcp-recA-vimA-vimE-vimF-aroG locus. This operon is essential for the maturation/activation/anchorage of the gingipains and regulation of other virulence factors of P. gingivalis. VimA is also important in oxidative stress resistance. Our data support a multifunctional role for VimA in modulating virulence in P. gingivalis possibly through its involvement in acetylation, that may affect A-LPS synthesis, protein sorting/transfer/anchorage and gene expression. In this project, we wish to extend these findings and to more fully clarify the VimA-dependent mechanism(s) of virulence regulation via acetylation. In bacteria including oral pathogens, the role of acetylation in virulence regulation has not been well characterized. The long term objective of our research program is to elucidate a comprehensive molecular mechanism(s) for virulence regulation in P. gingivalis as a prerequisite to the development of novel therapeutic interventions to aid in the control and prevention of diseases associated with this keystone pathogen. It is likely that VimA, which is involved in acetylation, may be a founding member of a novel transcriptional/post-translational control mechanism in Gram-negative anaerobic bacteria. The current application is designed for a comprehensive assessment of the multifunctional role of VimA. The specific aims: (1) To evaluate the role of acetylation in protein maturation in P. gingivalis. (2) To evaluate the effects of VimA-dependent acetylation on gingipain activation in P. gingivalis. Collectively, the results from this study will clarify the mechanistic role of VimA in virulence regulation in P. gingivalis. It should shed light on the acetylation regulatory network in P. gingivalis. It will generate a model system(s) that will yield important clues that will facilitate the development of novel therapeutic interventions to aid in te control and prevention of periodontal disease

描述（由适用提供）：牙龈卟啉单胞菌是一种黑色色素，革兰氏阴性的厌氧菌，是牙周疾病的重要病因，也与心血管疾病，类风湿关节炎和其他全身性疾病有关。牙龈疟原虫作为“基石病原体”的最新设计进一步凸显了其适应牙周口袋的有害炎症状况并破坏宿主 - 微生物稳态的能力，这部分负责牙周疾病中观察到的病理。为了生存并策划可能导致疾病的微生物/宿主活性，表明牙龈疟原虫潜力是一个复杂的调节网络，可能涉及转录和转录后机制。虽然调节牙龈疟原虫的致病潜力的关键要素是几种主要的表面蛋白/结构的翻译后修饰，但我们对该电路的组件和机制的理解存在差距。在本应用中要解决的特定假设是，通过乙酰化，新型VIMA（病毒调节）基因产物参与了牙龈疟原虫中几种主要表面蛋白的翻译后控制，包括牙龈成熟/激活。该假设是基于上一个资金期间的观察结果，我们表征了BCP-RECA-VIMA-VIMA-VIME-VIMF-AROG基因座。这部歌剧对于牙舞的成熟/激活/锚固至关重要，并调节了牙龈疟原虫的其他病毒因子。 VIMA在氧化应激抗性中也很重要。我们的数据支持VIMA通过参与乙酰化来调节牙龈疟原虫病毒的多功能作用，这可能会影响A-LPS合成，蛋白质分配/转移/锚定和基因表达。在这个项目中，我们希望扩展这些发现，并通过乙酰化来更完全阐明病毒调节的VIMA依赖机制。在包括口腔病原体在内的细菌中，乙酰化在病毒调节中的作用尚未得到很好的特征。我们研究计划的长期目标是阐明牙龈疟原虫调节病毒调节的综合分子机制，这是开发新的治疗干预措施的先决条件，以帮助控制和预防与这种基石病原体相关的疾病。参与乙酰化的VIMA可能是一个基础革兰氏阴性厌氧菌中新型转录/翻译后控制机制的成员。当前的应用旨在全面评估VIMA的多功能作用。具体目的：（1）评估乙酰化在蛋白质中的作用牙龈疟原虫的成熟。（2）评估依赖VIMA依赖性乙酰化对牙龈疟原虫激活的影响。总的来说，这项研究的结果将阐明VIMA在牙龈疟原虫中病毒调节中的机理作用。它应该阐明牙龈疟原虫的乙酰化调节网络。它将生成一个模型系统，该系统将产生重要线索将有助于开发新的热干预措施，以帮助控制和预防牙周疾病