BrpA in Virulence Modulation of Streptococcus mutans

 描述（由申请人提供）：尽管在预防和治疗方面取得了实质性进展，但龋齿（通常称为蛀牙或蛀牙）仍然是全球最常见和最昂贵的传染病之一。根据疾病预防控制中心的数据，每年相关的医疗保健费用超过800亿美元，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齿发病机制。致龋细菌在牙齿表面形成坚韧的生物膜，称为牙菌斑。在R 01 DE 019452的支持下，我们在过去五年中产生了开创性的证据，即生物膜调节蛋白BrpA（细胞包膜相关蛋白的LytR-CpsA-Psr家族的成员）在变形链球菌的细胞包膜生物发生和生物膜形成的调节中起关键作用。这一延续的总体目标是阐明BrpA如何调节S。变形链球菌的应激耐受反应和生物膜形成，这是人类龋齿的关键病原体的致病性的关键特征，并探索靶向BrpA在对抗S.变形菌和龋齿。在这项研究中，我们将 本研究采用酵母双杂交系统等现代分子生物学技术和传统的动物龋病模型相结合的方法，阐明了这一重要的链球菌蛋白表达的调控机制，鉴定了与BrpA相互作用的蛋白，揭示了BrpA对链球菌的调控机制。变形链球菌的病理生理学，和（iii）确定破坏BrpA对变形链球菌的能力的影响。变形菌在牙齿表面定居并引起龋齿。阐明参与调控BrpA表达的顺式和反式作用因子，揭示与BrpA相互作用的蛋白质及其在BrpA介导的功能中的作用，将构成我们不仅对BrpA，而且对LCP家族蛋白在S.变形杆菌和其他革兰氏阳性菌。这些发现有望促进制定/开发针对蛀牙和革兰氏阳性菌引起的潜在其他感染的新的综合策略。

 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.