BrpA in Virulence Modulation of Streptococcus mutans

BrpA 在变形链球菌毒力调节中的作用

基本信息

批准号：
9314529
负责人：
ZEZHANG TOM WEN
金额：
$ 49.26万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9314529
关键词：
ATP phosphohydrolase Affinity Amino Acids Animals Binding Sites Biochemical Biogenesis Biological Assay Cellular biology Centers for Disease Control and Prevention (U.S.)Childhood Communicable Diseases Complex Consensus Defect Dental Plaque Dental caries Development Disease Elements Etiology Family Formulation Fumarates Functional disorder Gene Fusion Gene Targeting Genes Genetic Transcription Goals Gram-Positive Bacteria Health Care Costs Homeostasis Human Infection Lesion Mediating Microbial Biofilms Modeling Modernization Molecular Mutagenesis Mutation Nature Nitrate Reductases Oxidative Stress Pathogenesis Pathogenicity Pharmacotherapy Phosphotransferases Play Predisposition Prevention Prevention strategy Production Protein Family Proteins Rattus Recombinants Regulation Reporter Reporter Genes Repression Role Seminal Serine Site Streptococcus Streptococcus mutans Tail Techniques Testing Therapeutic Threonine Trans-Activators United States Vaccination Virulence Waxes acid stress antimicrobial base cariogenic bacteria cell envelope cell growth regulation combat cost design drug candidate functional genomics genetic regulatory protein killings member mutant novel oral bacteria pathogen promoter public health relevance response small molecule inhibitor stress tolerance tooth surface trait yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Despite substantial progress in prevention and treatment, dental caries, commonly known as tooth decay or cavities, remains one of the most common and costly infectious diseases worldwide. According to the CDC, associated health care costs more than 80 billion dollars annually, and the rates of childhood caries in the United States are rising. Novel, comprehensive strategies are needed to effectively combat caries pathogenesis. Cariogenic bacteria form tenacious biofilms on the surface of teeth known as dental plaque. Supported by R01 DE019452, we have over the past five years generated seminal evidence that biofilm regulatory protein BrpA, a member of the LytR-CpsA-Psr family of cell envelope associated proteins, plays a critical role in regulation of cell envelope biogenesis and biofilm formation by Streptococcus mutans. The overall goals of this continuation are to elucidate how BrpA regulates S. mutans stress tolerance response and biofilm formation, traits critical to pathogenicity of this key etiological agent of human dental caries, and to explore the potential of targeting BrpA in strategy against S. mutans and dental caries. In this study, we will use an integrative approach that includes modern molecular and biochemical techniques, such as yeast two-hybrid system, and traditional animal caries model (i) to elucidate the mechanisms that govern the expression of this important streptococcal protein, (ii) to identify protein(s) tha interact with BrpA and uncover how BrpA regulates S. mutans pathophysiology, and (iii) to determine the effects of disrupting BrpA on the ability of S. mutans to colonize the tooth surface and cause carious diseases. Elucidation of cis- and trans-acting factors involved in regulation of BrpA expression and uncovering of proteins interactive with BrpA and their roles in BrpA-mediated functions will constitute a major breakthrough in our understanding of not only just BrpA, but also the LCP family of proteins in regulation of cellular biology in S. mutans and other Gram-positive bacteria. Such findings are expected to facilitate the formulation/development of novel comprehensive strategies against tooth decay and potentially other infections caused by Gram-positive bacteria.

描述（由申请人提供）：尽管在预防和治疗方面取得了重大进展，但龋齿（通常称为蛀牙或蛀牙）仍然是世界范围内最常见和最昂贵的传染病之一，据 CDC 称，相关医疗费用超过 80 美元。每年，美国的儿童龋齿发病率正在上升，需要新的、全面的策略来有效对抗龋齿的发病机制，致龋细菌在牙齿表面形成顽强的生物膜，称为牙菌斑。 R01 DE019452，我们在过去五年中获得了重要证据，表明生物膜调节蛋白 BrpA（细胞膜相关蛋白 LytR-CpsA-Psr 家族的成员）在调节链球菌细胞膜生物发生和生物膜形成中发挥着关键作用本研究的总体目标是阐明 BrpA 如何调节变形链球菌应激耐受反应和生物膜形成，这些特征对其致病性至关重要。人类龋齿的关键病因，并探索以 BrpA 为靶标对抗变形链球菌和龋齿的潜力。使用综合方法，包括现代分子和生化技术，例如酵母双杂交系统和传统动物龋齿模型（i）阐明控制这种重要链球菌蛋白表达的机制，（ii）识别蛋白质) 与 BrpA 相互作用并揭示 BrpA 如何调节变形链球菌病理生理学，以及 (iii) 确定破坏 BrpA 对变形链球菌在牙齿表面定殖的能力的影响阐明参与 BrpA 表达调节的顺式和反式作用因子，揭示与 BrpA 的蛋白质相互作用及其在 BrpA 介导的功能中的作用，将构成我们对 BrpA 和对 BrpA 的理解的重大突破。此外，LCP 家族蛋白在变形链球菌和其他革兰氏阳性细菌的细胞生物学调节中的作用预计将有助于制定/开发针对蛀牙和革兰氏阳性细菌引起的潜在其他感染的新型综合策略。