Regulation of Streptococcus mutans AtlA on the cell surface

变形链球菌 AtlA 对细胞表面的调节

• 批准号: 8702318
• 负责人: Sang-Joon Ahn
• 金额: $ 11.23万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-09 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702318
• 关键词: Architecture; Area; Autolysin; Autolysis; Bacteria; Bacterial Adhesins; Bacterial Physiology; Binding; Biogenesis; Biological Assay; Cell Wall; Cell surface; Cells; Complex; Critical Pathways; Cytokinesis; Cytolysis; Data; Dental caries; Development; Disease Management; Event; Future; In Vitro; Individual; Infective endocarditis; Libraries; Ligands; Membrane Proteins; Microbial Biofilms; Microscopic; Modeling; Molecular; Monitor; Mus; Operon; Oral cavity; Organism; Pathogenesis; Pathway interactions; Patients; Pharmacotherapy; Pilot Projects; Principal Investigator; Process; Proteins; Proteolytic Processing; Regulation; Regulatory Pathway; Research; Risk; Role; Series; Streptococcus gordonii; Streptococcus mutans; Structure; Surface; Testing; Therapeutic; base; cellular targeting; design; driving force; in vivo; inhibitor/antagonist; innovation; insight; killings; mouse model; mutant; novel; oral biofilm; oral streptococci; protein profiling; public health relevance; research study; screening; therapeutic target; tool; tooth surface

DESCRIPTION (provided by applicant): Development of a mature biofilm on the tooth surface is an important component of bacterial survival and pathogenesis in the oral cavity. Although over the past years, the complexity of the oral biofilm has been rapidly revealed, understanding how bacteria build up mature pathogenic biofilms in a well- defined way, is still lacking, leading to difficulty in identifying and designing new targets for anti-biofilm therapies. Toward this end, the study of the major Streptococcus mutans autolysin AtlA, shown to be required for biofilm maturation, is a new, but critical pathway for a more complete understanding for biofilm development of this organism. The demonstrated ability of the AtlA pathway to modulate cell surface remodeling is a major driving force for the studies outlined in this proposal, providing a new paradigm for the complex biofilm process particularly as related to the cell surface structure and remodeling process. Under this scope, we will focus our efforts in three interrelated areas. In Specific Aim1, we will elucidate how AtlA is functionally and structurally associated with the cell surface through analysis of repeat domains in the AtlA protein. In the Specific Aim 2, we hypothesize that surface localization and activity of AtlA are modulated primarily by the gene products encoded within the atlA operon. In this Aim, we also attempt to identify additional AtlA-associated components, enhancing our understanding of the architecture and function of AtlA on the cell surface. And in the Specific Aim 3, we will perform a pilot experiment in a mouse caries model to begin to analyze the in vivo impact of AtlA in S. mutans caries development. Overall, this application manipulates an as yet uncharacterized role of AtlA in S. mutans biofilm formation, and data derived from these proposed studies have a high potential to facilitate the development of innovative therapeutic strategies to treat dental caries, e.g. by interfering with the autolytic pathways necessary for the proper development of cariogenic biofilms. This project is also part of our long-term objective elucidating the molecular basis for biofilm maturation and its underlying mechanisms.

描述（由申请人提供）：牙齿表面成熟生物膜的形成是口腔细菌存活和发病机制的重要组成部分。尽管在过去几年中，口腔生物膜的复杂性已被迅速揭示，但仍然缺乏对细菌如何以明确的方式建立成熟致病性生物膜的了解，导致难以识别和设计抗生物膜疗法的新靶点。为了这个目的， 对主要变形链球菌自溶素 AtlA 的研究表明，AtlA 是生物膜成熟所必需的，对于更全面地了解该生物体的生物膜发育来说，这是一条新的但关键的途径。 AtlA 通路调节细胞表面重塑的能力是本提案中概述的研究的主要驱动力，为复杂的生物膜过程，特别是与细胞表面结构和重塑过程相关的生物膜过程提供了新的范例。在此范围内，我们将重点在三个相互关联的领域开展工作。在 Specific Aim1 中，我们将通过分析 AtlA 蛋白中的重复结构域来阐明 AtlA 如何在功能和结构上与细胞表面相关。在具体目标 2 中，我们假设 AtlA 的表面定位和活性主要由 atlA 操纵子内编码的基因产物调节。在这个目标中，我们还尝试识别其他与 AtlA 相关的成分，以增强我们对细胞表面 AtlA 的结构和功能的理解。在具体目标 3 中，我们将在小鼠龋齿模型中进行初步实验，以开始分析 AtlA 对变形链球菌龋齿发育的体内影响。总体而言，该应用操纵了 AtlA 在变形链球菌生物膜形成中尚未表征的作用，并且从这些拟议研究中获得的数据具有很大的潜力，可以促进治疗龋齿的创新治疗策略的开发，例如龋齿治疗。通过干扰致龋生物膜正常发育所必需的自溶途径。该项目也是我们阐明生物膜成熟的分子基础及其潜在机制的长期目标的一部分。