A novel mechanism of virulence control in Porphyromonas gingivalis

牙龈卟啉单胞菌毒力控制的新机制

• 批准号: 10296292
• 负责人: Jorge Frias-Lopez
• 金额: $ 69.29万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296292
• 关键词: Abscess; Address; Adult; Anabolism; Animal Model; BCAR1 gene; Bacteria; Bacteriophages; Cell Line; Cell Survival; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cobalamin; Complex; Cultured Cells; DNA; DNA Repair; Data; Development; Disease; Disease Progression; Epithelial Cells; Francisella; Gene Expression; Genes; Genetic; Gingiva; Goals; Health; Health Transition; Human; IL8 gene; Immune; Immune response; Immunity; Infection; Inflammation; Inflammatory; Innate Immune Response; Interleukin-1 beta; Iron; Knowledge; Libraries; Measures; Metabolism; Modeling; Molecular; Moths; Mus; Operon; Oral; Outcome; Pathogenicity; Periodontal Diseases; Periodontitis; Play; Porphyromonas gingivalis; Production; Proteins; Proteolysis; Pseudomonas aeruginosa; Publishing; Reporting; Research; Role; Sampling; Signal Transduction; Site; System; TLR2 gene; TLR4 gene; TNF gene; Testing; Therapeutic; Tissues; Toll-like receptors; Tooth structure; Viral; Virulence; Virulence Factors; Waxes; Work; base; bone loss; experimental study; gene function; human microbiota; in vivo; infancy; keratinocyte; macrophage; metatranscriptome; microbial; microbial community; mutant; neutrophil; novel; oral infection; pathogen; periodontopathogen; polymicrobial disease; prevent; programs; transcriptome

Abstract Porphyromonas gingivalis is a major pathogen of severe adult periodontitis, a polymicrobial disease caused by the coordinated action of a complex microbial community that leads to inflammation of tissues supporting the teeth. A central hurdle limiting progress in periodontal disease research is the paucity of information detailing microbial signals that correlate with clinical progression at a site from health to disease. Filling this void, we recently reported metatranscriptome findings of the microbial community from human clinical samples during periodontal disease progression and discovered that CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-associated proteins in the periodontopathogen P. gingivalis were highly up-regulated only at those sites that progressed. CRISPRs-Cas systems are used by bacteria to prevent foreign DNA incorporation, as occurs with a viral attack. The goal of this research program is to understand the role that CRISPR-Cas systems have on virulence determinants of important periodontopathogens during disease progression. A comprehensive analysis of the mutants will provide information required to increase our understanding of not only CRISPR gene function, but also the contribution of these novel genes to virulence. To this end we propose the following Specific Aims: Aim 1. Identify targeted endogenous genes comparing transcriptome profiles of the wild-type and the mutants growing intracellularly. Aim 2. Determine the impact of CRISPR-associated genes on the innate immune host responses to P. gingivalis. Aim 3. Aim 3. Determine the role of CRISPR-Cas genes in the pathogenicity of P. gingivalis. We expect that this knowledge will facilitate the development of targeted approaches to prevent and treat periodontitis by inhibiting specific Cas proteins essential for virulence. Such results will fundamentally advance our understanding that such systems have in the metabolism of periodontal pathogens besides their traditional role assigned as a mechanism of protection against foreign DNA. We believe that the team we have assembled for this project has all the qualifications to accomplish successfully the goals proposed in the present application.

抽象的 牙龈卟啉单胞菌是严重成人牙周炎的主要病原体，这是由 复杂的微生物群落的协调作用，导致组织的炎症 牙齿。牙周疾病研究中限制进展的主要障碍是信息细节的匮乏 与现场从健康到疾病的临床进展相关的微生物信号。填补这个空白，我们 最近报道 牙周疾病进展，发现CRISPR（定期散布短短 牙周病原体牙龈疟原虫中的alindromic重复序列）仅上调了牙龈牙周病原体 在那些进步的网站上。细菌使用CRISPRS-CAS系统来防止外国DNA 与病毒攻击发生的合并。该研究计划的目的是了解 CRISPR-CAS系统对疾病中重要牙周病的毒力决定因素具有 进展。对突变体的全面分析将提供增加我们的信息 不仅了解CRISPR基因功能，还了解这些新基因对毒力的贡献。到 我们提出以下具体目标： AIM 1。确定比较野生型和突变体转录组轮廓的靶向内源基因 细胞内生长。 目标2。确定与CRISPR相关基因对先天免疫宿主对P的影响。 牙龈。 目标3。目标3。确定CRISPR-CAS基因在牙龈疟原虫致病性中的作用。 我们希望这些知识将有助于开发有针对性的方法来预防和治疗 牙周炎通过抑制毒力必不可少的特异性CAS蛋白。这样的结果从根本上将推动我们的 了解此类系统在牙周病原体的代谢中还具有传统作用 被指定为防止外国DNA的保护机制。我们相信我们为此组建了团队 项目具有所有资格，可以成功实现本应用程序中提出的目标。