Molecular Aspects of Oral Plaque Formation

描述（由申请人提供）：牙周病是人类最常见的感染之一，具有多微生物病因学，其中微生物组表现出协同致病性。作为研究多微生物协同作用的模型系统，我们正在研究牙龈卟啉单胞菌-S。戈登互动S. gordonii，斑的早期殖民者 生物膜为致病性更强的晚期定植菌牙龈卟啉单胞菌提供附着基质。接触依赖性信号传导和代谢物感知引发牙龈卟啉单胞菌的进一步积累和双物种群落的发展。种间共粘附是由牙龈卟啉单胞菌的短菌毛（由Mfa 1结构亚基组成）介导的，该菌毛与链球菌的Ssp表面蛋白接合。gordonii。在SspB内，跨越残基1167-1193的区域（命名为BAR）内的几个氨基酸基序决定结合活性和特异性。社区发展的发展和后来的限制取决于牙龈卟啉单胞菌内酪氨酸磷酸化（通过激酶Ptk 1）和去磷酸化（通过磷酸酶Ltp 1）的平衡，这控制了社区效应物（如Mfa 1和LuxS）的表达。这种酪氨酸磷酸化依赖的信号转导途径也集中在编码蛋白酶的表达基因上，并形成牙龈卟啉单胞菌和沙门氏菌的双种群落。在鼠牙槽骨损失模型中，与单独的任一种相比，Gordonii更具致病性。本研究的目的是：i）表征与SspB的BAR结构域相互作用的Mfa 1的结构和功能基序; ii）确定牙龈卟啉单胞菌酪氨酸激酶Ptk 1在控制与SspB的异型群落发育的调控网络中的作用。gordonii;和iii）确定牙龈卟啉单胞菌对调节群落发育和致病潜力的链球菌代谢物4-氨基苯甲酸酯（pABA）的反应。这些目标的成功实现将为牙龈卟啉单胞菌Mfa 1菌毛粘附素的结构和功能提供新的信息。此外，我们将解开酪氨酸激酶（Ptk 1）和磷酸酶（Ltp 1）的活动之间的相互作用的信号转导事件，调节社区的发展。我们还将产生关于代谢物传感及其在社区发展和致病潜力中的作用的新信息。我们广泛的长期目标是将这一基本机制信息转化为针对致病性社区抑制的治疗干预的新靶点的鉴定。由于单一靶点干预的效用有限，并且尚未在牙周治疗选择方面取得任何重大进展，因此干扰致病菌群发展的多个组成部分，包括粘附和成熟事件，可能具有更大的成功可能性。

DESCRIPTION (provided by applicant): Periodontal disease, one of the most common infections of humans, has a polymicrobial etiology whereby groups of microorganisms exhibit synergistic pathogenicity. As a model system for the study of polymicrobial synergy we are investigating P. gingivalis-S. gordonii interactions. S. gordonii, an early colonizer of the plaque biofilm, provides an attachment substratum for the more pathogenic later colonizer P. gingivalis. Contact dependent signaling and metabolite perception initiate further accumulation of P. gingivalis and the development of a dual species community. Interspecies coadhesion is mediated by the short fimbriae (comprised of the Mfa1 structural subunit) of P. gingivalis that engage the Ssp surface proteins of S. gordonii. Within SspB several amino acid motifs within a region spanning residues 1167-1193 (designated BAR), dictate binding activity and specificity. Development, and later constraint, of community development depends on the balance of tyrosine phosphorylation (through the kinase Ptk1) and dephosphorylation (through the phosphatase Ltp1) within P. gingivalis, which controls expression of community effectors such as Mfa1 and LuxS. This tyrosine (de)phosphorylation dependent signal transduction pathway also converges on the expression genes encoding proteases, and a dual species community of P. gingivalis and S. gordonii is more pathogenic compared to either species alone in a murine alveolar bone loss model. The objectives of this study are to: i) characterize the structural and functional motifs of Mfa1 that interact with the BAR domain of SspB; ii) define the role of the P. gingivalis tyrosine kinase Ptk1 in regulatory networks that control heterotypic community development with S. gordonii; and iii) determine the responses of P. gingivalis to the streptococcal metabolite 4-aminobenzoate (pABA) that regulate community development and pathogenic potential. Successful completion of these objectives will provide novel structure and function information on the P. gingivalis Mfa1 fimbrial adhesin. In addition, we will unravel the interplay between tyrosine kinase (Ptk1) and phosphatase (Ltp1) activities in the signal transduction events that regulate community development. We will also generate novel information regarding metabolite sensing and its role in both community development and pathogenic potential. Our broad long-term goal is to translate this fundamental mechanistic information into the identification of novel targets for therapeutic intervention directed toward pathogenic community inhibition. As single target intervention can have limited utility, and has yet to yield any significant advances in periodontal therapeutic options, interference with multiple components of pathogenic community development, including adhesive and maturation events, may have a greater likelihood of success.