Treponema denticola, complement regulatory proteins and periodontal disease

齿垢密螺旋体、补体调节蛋白和牙周病

• 批准号: 7208842
• 负责人: RICHARD T MARCONI
• 金额: $ 34.23万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7208842
• 关键词: Adherence; Affect; Antibody Formation; Bacterial Adhesins; Binding; Biological; Cell Line; Cells; Complement; Complement Factor H; Development; Disease; Economics; Extracellular Matrix; Human; Immune; Individual; Infection; Integration Host Factors; Intervention; Life; Lipoproteins; Microbial Biofilms; Molecular; Mutagenesis; Numbers; Oral; Outcome; Pathogenesis; Patients; Penetration; Periodontal Diseases; Periodontitis; Play; Preventive Intervention; Production; Proteins; RGD (sequence); Research Personnel; Role; Specificity; Sushi Domain; Tissues; Treponema denticola; Virulence; adhesion receptor; genetic regulatory protein; insight; microbial; novel; pathogen

DESCRIPTION (provided by applicant): Periodontal disease will affect most individuals at some point in their life and its economic impact is enormous. Periodontitis results from a combination of host factors and a polymicrobial infection of normal flora origin. Disease results when an imbalance in numbers of each species develops. One contributor to periodontal disease is Treponema denticola (Td). We demonstrate that Td binds the complement regulatory protein, factor H like protein 1 (FHL-1) via an 11.5 kDa Td lipoprotein, designated, FhbB. FhbB is the only known protein produced by a microbial pathogen that specifically binds FHL-1 and not FH. This unique binding specificity provides possible insight into the biological rationale of FHL-1 binding by Td. In addition to its complement regulatory role, FHL-1 also has important cell adhesin and cell spreading activities. Several anchorage dependent cell lines have been demonstrated to bind to an FHL-1 matrix. The binding occurs through an RGD motif of FHL-1 that is located with a domain referred to as a short consensus repeat (SCR) 4. FHL-1 also interacts with the extracellular matrix (ECM) of tissue via this its RGD adhesion receptor recognition sequence. It is our hypothesis that the binding of cell or ECM anchored FHL-1 by the T. denticola FhbB protein plays a central role in several critical aspects of T. denticola pathogenesis including adherence, biofilm formation, tissue penetration and immune evasion. The studies proposed here fill an important niche in the study of T. denticola pathogenesis and of the biological role of FHL-1 binding by oral microflora and will advance our general understanding of the molecular mechanisms associated with the development and progression of periodontal disease. The Specific Aims of this application are: 1: Analysis of fhbB expression and production in the human host and assessment of the anti- FhbB antibody response during periodontal disease; 2: Identification of the molecular determinants of FhbB involved in FHL-1 binding; and 3) Analysis of the role of FhbB and FHL-1 binding in T. denticola pathogenesis through allelic exchange mutagenesis and complementation. General description: This application investigates a novel virulence mechanism employed by a causative agent of periodontal disease. The outcome of these analyses will allow for the development of new preventive and intervention strategies for periodontal disease.

描述（由申请人提供）：牙周病会影响大多数人在他们的生活中的某个时候，其经济影响是巨大的。牙周炎是宿主因素和正常植物群来源的多种微生物感染共同作用的结果。当每一物种的数量不平衡发展时，就会产生疾病。牙周病的一个贡献者是齿垢密螺旋体（Td）。我们证明，Td结合补体调节蛋白，因子H样蛋白1（FHL-1）通过11.5 kDa的Td脂蛋白，指定，FhbB。FhbB是唯一已知的由微生物病原体产生的特异性结合FHL-1而不是FH的蛋白质。这种独特的结合特异性为Td与FHL-1结合的生物学原理提供了可能的见解。除了其补体调节作用外，FHL-1还具有重要的细胞粘附素和细胞铺展活性。已经证明几种锚定依赖性细胞系与FHL-1基质结合。结合通过FHL-1的RGD基序发生，该基序位于称为短共有重复序列（SCR）4的结构域。FHL-1还通过其RGD粘附受体识别序列与组织的细胞外基质（ECM）相互作用。我们假设T. Denticola FhbB蛋白在T.齿垢的发病机制包括粘附、生物膜形成、组织渗透和免疫逃避。本文的研究填补了T.本研究旨在阐明牙周炎的发病机制和口腔微生物FHL-1结合的生物学作用，并将促进我们对牙周病发生和进展相关分子机制的全面理解。本申请的具体目的是：1：分析人宿主中fhbB的表达和产生并评估牙周病期间的抗FhbB抗体应答; 2：鉴定参与FHL-1结合的FhbB的分子决定簇;和3）分析FhbB和FHL-1结合在T.通过等位基因交换突变和互补作用的齿垢致病机制。一般描述：本申请研究了牙周病病原体采用的一种新的毒力机制。这些分析的结果将允许开发新的牙周病预防和干预策略。