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：
10661800
负责人：
ZEZHANG TOM WEN
金额：
$ 49.23万
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：
2009-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661800
关键词：
Affect Anabolism Bacteria Binding Biochemical Biogenesis Bioinformatics Biological Assay Biophysics Cell Wall Cell physiology Communicable Diseases Cost of Illness Culture Media DNA Footprint Dental Plaque Dental caries Development Dose EMSA Enzymes Epitopes Foundations Functional disorder Genetic Genetic Transcription Glucans Glucosyltransferases Goals Gram-Positive Bacteria Growth Health Care Costs Human In Vitro Lead Lesion Ligands Ligase Luciferases Mediating Microbial Biofilms Modeling Modernization Molecular Mouth Diseases Mutagenesis Northern Blotting Odontogenesis Organic Chemistry Outcome Study Pathogenesis Pharmaceutical Preparations Play Polymers Prevention Prevention strategy Production Protein Family Proteins RNA Rattus Recombinants Regulation Reporter Role S-Adenosylhomocysteine S-Adenosylmethionine Seminal Solid Streptococcus Streptococcus mutans Structure Surface Techniques Testing Transcript Virulence X-Ray Crystallography anticaries cariogenic bacteria cell envelope combat cost dental biofilm genetic regulatory protein in silico in vivo insight lead optimization mutant novel novel strategies novel therapeutics oral microbial community posttranscriptional premature protein complex screening small molecule small molecule libraries structural biology tool tooth surface transcription factor transcription termination

项目摘要

SUMMARY 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 USA tens of billions of dollars annually. 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 six years generated seminal evidence that biofilm regulatory protein BrpA, a multi-functional surface- associated protein, plays a critical role in regulation of Streptococcus mutans cell envelope biogenesis and biofilm formation and its ability to cause carious lesions. The overall goals of this competitive renewal are to uncover the complexity of the molecular mechanisms that govern the expression of brpA and the mechanisms how BrpA mediates intra- and inter-species biofilm formation, and to explore the potential of the lead small molecules in targeting BrpA and modulation of S. mutans virulence. We will use an integrative approach including various modern molecular, biochemical and bioinformatics techniques to identify the transcriptional and post-transcriptional factors that govern the regulation of brpA expression, and to determine the different binding epitopes and build the ligand-protein complex model to guide structural and functional analysis of BrpA. In addition, we will use organic chemistry along with various function assays and in vivo rat caries model to optimize the efficacy and selectivity of the selected lead small inhibitory molecules against S. mutans and to explore their potential in novel anticaries strategy. Successful implementation of this proposal could prove to be major advances in our understanding of BrpA in S. mutans pathophysiology, which could ultimately be applied to the LCP proteins in other Gram-positive bacteria. The findings on small molecules are expected to provide a solid foundation for the development of novel strategies against S. mutans and human dental caries.

概括尽管在预防和治疗方面取得了重大进展，但龋齿（俗称蛀牙）或蛀牙，仍然是全世界最常见和最昂贵的传染病之一。根据疾病预防控制中心以及相关的医疗保健每年花费美国数百亿美元。新颖、全面需要有效对抗龋齿发病机制的策略。致龋菌形成顽强牙齿表面的生物膜称为牙菌斑。在R01 DE019452的支持下，我们已经超过了过去六年产生的开创性证据表明生物膜调节蛋白 BrpA 是一种多功能表面相关蛋白，在变形链球菌细胞包膜生物发生的调节中起着关键作用，生物膜的形成及其引起龋损的能力。此次竞争性更新的总体目标是揭示控制 brpA 表达的分子机制的复杂性和 BrpA 介导物种内和物种间生物膜形成的机制，并探索其潜力靶向 BrpA 和调节变形链球菌毒力的先导小分子。我们将使用一个综合方法，包括各种现代分子、生物化学和生物信息学技术识别控制 brpA 表达调节的转录和转录后因子，并确定不同的结合表位并建立配体-蛋白质复合物模型来指导 BrpA 的结构和功能分析。此外，我们将使用有机化学以及各种功能测定和体内大鼠龋齿模型，以优化所选先导化合物的功效和选择性针对变形链球菌的小抑制分子，并探索它们在新型防龋策略中的潜力。该提案的成功实施可能会极大地增进我们对 BrpA 的理解变形链球菌病理生理学，最终可以应用于其他革兰氏阳性菌中的 LCP 蛋白细菌。小分子的研究结果有望为小分子药物的开发提供坚实的基础。对抗变形链球菌和人类龋齿的新策略。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Analysis of Fluoride Content in Alternative Milk Beverages.

替代乳饮料中氟化物含量的分析。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Townsend, Janice A;Thompson, Tatyana;Vaughn, Skylar;Wang, Yapin;Yu, Qingzhao;Xu, Xiaoming;Wen, Zezhang T
通讯作者：
Wen, Zezhang T

BrpA is involved in regulation of cell envelope stress responses in Streptococcus mutans.

BrpA 参与变形链球菌细胞包膜应激反应的调节。

DOI：
发表时间：
2012-04
期刊：
影响因子：
4.4
作者：
Bitoun, J P;Liao, S;Yao, X;Ahn, S;Isoda, R;Nguyen, A H;Brady, L J;Burne, R A;Abranches, J;Wen, Z T
通讯作者：
Wen, Z T

Streptococcus mutans Displays Altered Stress Responses While Enhancing Biofilm Formation by Lactobacillus casei in Mixed-Species Consortium.

变形链球菌显示出改变的应激反应，同时增强混合物种联盟中干酪乳杆菌的生物膜形成。

DOI：
发表时间：
2017
期刊：
影响因子：
0
作者：
Wen, Zezhang T;Liao, Sumei;Bitoun, Jacob P;De, Arpan;Jorgensen, Ashton;Feng, Shihai;Xu, Xiaoming;Chain, Patrick S G;Caufield, Page W;Koo, Hyun;Li, Yihong
通讯作者：
Li, Yihong

Transcriptional repressor Rex is involved in regulation of oxidative stress response and biofilm formation by Streptococcus mutans.

转录抑制因子 Rex 参与变形链球菌氧化应激反应和生物膜形成的调节。