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

Ser/Thr 蛋白激酶 PknB 作为减少变形链球菌生态的靶点

• 批准号: 8283716
• 负责人: Jens Kreth
• 金额: $ 11.1万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-19 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8283716
• 关键词: Adult; Affect; Caries prevention; Communicable Diseases; Competence; Dental caries; Developing Countries; Development; Disease; Etiology; Excision; Gene Expression; Goals; Growth; In Vitro; Individual; Intervention; Knowledge; Learning; Microbial Biofilms; Monitor; Oral cavity; Oral health; Phosphorylation; Phosphotransferases; Population; Predisposition; Prevalence; Process; Production; Protein Dynamics; Protein Kinase; Proteomics; Regulation; Reporter; Resistance; Role; Signal Transduction; Streptococcus mutans; Stress; bacteriocin; biological adaptation to stress; cell envelope; design; fitness; inhibitor/antagonist; member; novel therapeutics; oral biofilm; prevent; protein expression; response; sensor; success

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.

描述（由申请人提供）：蛀牙或龋齿是影响全世界十分之一的人中有九分之九的最常见的传染病之一，而贫困人群中有较高的比率。口服生物膜成员链球菌突变在龋齿病因中的作用已得到充分确立。因此，口服生物膜中的链球菌水平的管理将对口腔健康有益并防止龋齿发育。该项目着重于真核样的Ser/Thr蛋白激酶PKNB作为抗S。突变目标。 PKNB是包膜相关应力的重要传感器，并触发各自的细胞反应，以增加链球菌的抗压力。最近，我们能够证明PKNB缺乏对生态压力的缺乏症状的敏感性增加。本研究的目的是确定一种干扰PKNB依赖性压力适应的最佳方法。在AIM 1中，我们建议在生物膜生长的背景下确定PKNB表达的水平和PKNB的定位水平。通过这种方法，我们将获得有关链球菌生物膜特异性基因表达的重要信息，并确定PKNB中可访问的结构靶标。在AIM 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，以鉴定链球菌特异性PKNB干扰的潜在附加细胞内靶标。这项研究将扩大对PKNB依赖调节的知识，并有助于制定可能的新型治疗策略来预防龋齿。 公共卫生相关性：龋齿是一种常见的传染病，导致受影响的个体不适。链球菌突变在龋齿发育中的病因作用已得到充分证明。该项目研究了S. mutans压力反应的特定组成部分，目的是确定干扰应力适应过程的最佳方法。对此过程的详细理解将为S. Mutans特定的干预措施提供重要的新信息，以防止龋齿。