Expression of clp genes in Streptococcus mutans

clp基因在变形链球菌中的表达

基本信息

批准号：
8812793
负责人：
Indranil Biswas
金额：
$ 37.5万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8812793
关键词：
ATP phosphohydrolase Acids Adaptor Signaling Protein Adult Affect Antibiotics Arginine Back Bacteria Bacterial Proteins Binding Biochemical Biochemical Genetics C-terminal Child Communities Complex DNA Binding DNA Binding Domain Data Dental Plaque Dental caries Developed Countries Development Drug Targeting Elements Environment Expenditure Family Future Gene Expression Gene Expression Regulation Genes Genome Goals Growth Health Helix-Turn-Helix Motifs Homologous Gene Human In Vitro Infective endocarditis Knowledge Lead Light Mediating Metabolism Microbial Biofilms Molecular Molecular Chaperones Mutagenesis Mutate N-terminal Nutrient Oral cavity Organism Oxidative Stress Pathogenesis Peptide Hydrolases Phosphorylation Play Production Protein Family Proteins Proteolysis Quality Control Regulation Regulator Genes Regulatory Pathway Role Schools Sequence Homology Serine Protease Sigma Factor Streptococcus Streptococcus mutans Streptococcus pneumoniae Streptococcus pyogenes Stress Substrate Specificity System Tandem Repeat Sequences Temperature Transcription Coactivator Transcription Repressor/Corepressor Up-Regulation Virulence acid stress bacteriocin biological adaptation to stress cis acting element dimer drug development environmental flux feeding genetic approach global health in vitro Assay in vivo insight mutant novel novel therapeutics pathogen prevent promoter protein degradation response stress tolerance stressor thermal stress tooth surface

项目摘要

DESCRIPTION (provided by applicant): Streptococcus mutans is considered as the major etiological agent in dental caries. S. mutans is also an important agent of infective endocarditis. The organism colonizes the oral cavity by forming diverse, multispecies biofilms on the tooth surface, known as dental plaque. This pathogen has developed multiple mechanisms to adapt and to flourish in the hostile environment of the oral cavity. S. mutans has the ability to respond rapidly and efficiently to various environmental fluxes, including severe nutrient limitation, fluctuations in pH and temperature, and changes in oxidative and osmotic tensions. Exposure of bacteria to these adverse environments can induce a stress tolerance response through expression of a wide variety of genes that provides cross-protection against diverse environmental challenges. Stress tolerance genes are regulated by unique groups of transcriptional regulators, including alternate sigma factors. However, unlike other pathogens, S. mutans and other streptococci do not encode any alternate sigma factors. On the other hand, some genes that putatively function in stress responses in other bacteria are present in the S. mutans genome, but their role in stress and virulence has not been investigated in S. mutans in great detail. One such group is the Clp (caseinolytic protease) family of proteins that are involved in thermal and oxidative stress responses. The Clp family is composed of a small cytoplasmic serine protease, called ClpP, and various ATPases. S. mutans encodes five Clp ATPases and ClpP associates with a partner Clp ATPase to form a functional complex that specifically targets damaged or misfolded proteins for degradation or translocation. While the ATPase component determines the substrate specificity, ClpP degrades the damaged protein. In most pathogens, ClpP plays a very important role in virulence. For example, in S. mutans, ClpP is required for optimal biofilm formation and acid-tolerance response. Although ClpP play important roles for the pathogenesis, very little is known about the regulation of the clp genes in this pathogen. Regulation of the clp genes is very complex, and can vary significantly depending on the organism. The main goal of this proposal is to gain insight into the expression of the clpP gene during S. mutans growth under normal and stressful conditions. Furthermore, we also propose to study an important and unique transcriptional repressor, CtsR, which is important for clp genes, including clpP, expression during adaptive response. We anticipate that completion of this project will lead to the identification of novel regulatory pathway for expression of stress response genes in S. mutans. Moreover, knowledge acquired from this project can also be extended to analysis of other important gram-positive pathogens such as S. pnemoniae and S. pyogenes, and may lead to the identification of novel drug targets.

描述（由申请人提供）：变形链球菌被认为是龋齿的主要病原体。变形链球菌也是感染性心内膜炎的重要病原体。该生物体通过在牙齿表面形成多样化、多物种的生物膜（称为牙菌斑）而在口腔中定殖。这种病原体已经发展出多种机制来适应口腔的恶劣环境并在其中繁衍生息。变形链球菌能够快速有效地响应各种环境通量，包括严重的营养限制、pH 和温度的波动以及氧化和渗透压的变化。细菌暴露在这些不利环境中可以通过表达多种基因来诱导应激耐受反应，这些基因提供针对不同环境挑战的交叉保护。应激耐受基因受到独特的转录调节因子组的调节，包括替代西格玛因子。然而，与其他病原体不同，变形链球菌和其他链球菌不编码任何替代西格玛因子。另一方面，一些在其他细菌的应激反应中发挥作用的基因也存在于变形链球菌基因组中，但它们在应激和毒力中的作用尚未在变形链球菌中得到详细研究。其中一组是参与热和氧化应激反应的 Clp（酪蛋白分解酶）蛋白质家族。 Clp 家族由一种称为 ClpP 的小型细胞质丝氨酸蛋白酶和各种 ATP 酶组成。变形链球菌编码五种 Clp ATP 酶，ClpP 与伙伴 Clp ATP 酶结合形成功能复合物，专门针对受损或错误折叠的蛋白质进行降解或易位。 ATP 酶成分决定底物特异性，而 ClpP 则降解受损的蛋白质。在大多数病原体中，ClpP 在毒力中起着非常重要的作用。例如，在变形链球菌中，ClpP 是最佳生物膜形成和耐酸反应所必需的。尽管 ClpP 在发病机制中发挥重要作用，但对该病原体中 clp 基因的调控知之甚少。 clp 基因的调节非常复杂，并且根据生物体的不同可能有很大差异。该提案的主要目标是深入了解正常和应激条件下变形链球菌生长过程中 clpP 基因的表达。此外，我们还建议研究一种重要且独特的转录抑制因子CtsR，它对于适应性反应期间clp基因（包括clpP）的表达非常重要。我们预计该项目的完成将导致识别变形链球菌应激反应基因表达的新调控途径。此外，从该项目中获得的知识还可以扩展到其他重要的革兰氏阳性病原体（例如肺炎链球菌和化脓性链球菌）的分析，并可能导致新药物靶点的识别。