BrpA in Virulence Modulation of Streptococcus mutans

 描述(申请人提供)：尽管在预防和治疗方面取得了实质性进展，但龋齿，通常被称为龋齿或龋齿，仍然是世界上最常见和最昂贵的传染病之一。根据美国疾病控制与预防中心的数据，相关的医疗保健每年花费超过800亿美元，而且美国儿童龋齿的发病率正在上升。需要新的、全面的策略来有效地对抗龋病的发病机制。致龋菌在牙齿表面形成坚韧的生物膜，称为牙菌斑。在R01 DE019452的支持下，我们在过去的五年中产生了种子证据，表明生物膜调节蛋白BrPA是LytR-CPSA-PSR细胞膜相关蛋白家族的成员，在调节变形链球菌的细胞膜生物发生和生物膜形成中发挥着关键作用。本继续的总体目标是阐明BrPA如何调节变形链球菌的应激耐受反应和生物膜的形成，这些特征对这种人类龋病的关键病原体的致病性至关重要，并探索靶向BrPA在防治变形链球菌和龋齿策略中的潜力。在这项研究中，我们将 使用包括现代分子和生化技术的综合方法，如酵母双杂交系统和传统的动物龋病模型，(I)阐明这种重要的链球菌蛋白表达的机制，(Ii)鉴定与BrPA相互作用的蛋白质(S)，并揭示BrPA如何调节变形链球菌的病理生理，以及(Iii)确定干扰BrPA对变形链球菌定植到牙齿表面并导致龋病的能力的影响。阐明参与BrPA表达调控和与BrPA相互作用的蛋白的顺式和反式作用因子及其在BrPA介导的功能中的作用，将是我们对BrPA以及LCP家族蛋白在变形链球菌和其他革兰氏阳性细菌细胞生物学调控中的重要突破。预计这些发现将有助于制定/开发新的综合战略，以预防龋齿和潜在的由革兰氏阳性细菌引起的其他感染。

 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.