Ser/Thr protein kinase PknB as target to decrease Streptococcus mutans ecological

描述（由申请人提供）：蛀牙或龋齿是最常见的传染病之一，影响全球十分之九的人，贫困群体的发病率更高。口腔生物膜成员变形链球菌在龋齿病因学中的作用已经得到很好的确立。管理S。因此，口腔生物膜中的变聚糖水平将有益于口腔健康并防止龋齿发展。本项目主要研究类真核生物丝氨酸/苏氨酸蛋白激酶PknB作为抗S.变形目标PknB是一个重要的传感器的信封相关的压力和触发相应的细胞反应，以增加S。变形菌胁迫抗性。最近，我们能够证明PknB缺陷菌株对生态压力的敏感性增加。本研究的目的是确定一个最佳的方法来干扰PknB依赖的压力适应。在目的1中，我们提出确定在生物膜生长的背景下PknB的表达和定位的水平。通过这种方法，我们将获得关于S的重要信息。变形杆菌生物膜特异性基因表达和鉴定PknB中可接近的结构靶点。在目标2中，我们还将鉴定下游PknB激酶底物，并确定磷酸化级联反应，以鉴定S.变形杆菌特异性PknB干扰。这项研究将扩大PknB依赖性调节的知识，并有助于开发可能的新的治疗策略，以防止龋齿。 与公共卫生的关系：龋齿是一种常见的传染病，会使受影响的人感到相当不适。变形链球菌在龋病发展中的病因学作用已被充分证明。本项目研究了S.变形菌的应激反应，目的是确定干扰应激适应过程的最佳方法。对这一过程的详细了解将为S.预防龋齿的具体干预措施。

DESCRIPTION (provided by applicant): Tooth decay or dental caries is one of the most common infectious diseases affecting nine out of ten individuals worldwide with higher rates among underprivileged groups. The role of oral biofilm member Streptococcus mutans in the etiology of dental caries has been well established. Management of S. mutans levels in the oral biofilm would therefore be beneficial for oral health and prevent caries development. This project focuses on the eukaryotic-like Ser/Thr protein kinase PknB as an anti-S. mutans target. PknB is an important sensor of envelope related stress and triggers a respective cellular response to increase S. mutans stress resistance. Recently, we were able to demonstrate the increased susceptibility of a PknB deficient strain towards ecological stress. The goal of the present study is to identify an optimal approach to interfere with PknB dependent stress adaptation. In Aim 1 we propose to determine the levels of pknB expression and localization of PknB in the context of biofilm growth. With this approach we will obtain important information about S. mutans biofilm specific gene expression and identify accessible structural targets in PknB. In Aim 2 we will also identify downstream PknB kinase substrates and determine the phosphorylation cascade to identify potential additional intracellular targets for S. mutans specific PknB interference. This study will expand the knowledge of PknB dependent regulation and help to develop possible novel therapeutic strategies to prevent caries. PUBLIC HEALTH RELEVANCE: Dental caries is a common infectious disease causing considerable discomfort in affected individuals. The etiological role of Streptococcus mutans in caries development has been well documented. This project investigates a specific component of S. mutans stress response with the goal of determining the optimal approach to interfere with the stress adaptation process. A detailed understanding of this process will provide important new information for S. mutans specific interventions to prevent dental caries.