Defining the role of post-translational regulation by extracellular proteases in the pathogenesis of Staphylococcus aureus osteomyelitis
确定细胞外蛋白酶翻译后调节在金黄色葡萄球菌骨髓炎发病机制中的作用
基本信息
- 批准号:10675639
- 负责人:
- 金额:$ 45.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-06-15 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AmputationAnimal ModelAntibiotic TherapyBeliefBone Remodelling PathwayBone remodelingClinicalDebridementExhibitsFoundationsGenesGenus staphylococcusGoalsHost DefenseHumanImmune responseIn VitroIndividualInfectionInflammatory ResponseInvadedLaboratoriesMammalian CellMediatingMethicillinMethicillin ResistanceMicrobial BiofilmsModelingMutationNutrientOperative Surgical ProceduresOsteoblastsOsteoclastsOsteomyelitisPathogenesisPeptide HydrolasesPhenotypePlayPost-Translational RegulationProductionProteinsProteomeProteomicsReportingResistanceRoleSepsisStaphylococcus aureusStaphylococcus aureus infectionSurfaceTherapeuticTimeTissuesVirulenceVirulence Factorsboneclinically relevantcytotoxicityexperimental studyextracellularin vivomutantnovelnovel therapeutic interventionpathogenic bacteriaprophylactic
项目摘要
SUMMARY ABSTRACT
We have demonstrated that mutation of the staphylococcal accessory regulatory (sarA) in Staphylococcus
aureus results in an increase in the production of extracellular proteases to a degree that limits biofilm
formation, limits cytotoxicity for mammalian cells including osteoblasts and osteoclasts, and limits the
accumulation of both surface-associated and extracellular virulence factors. We have also demonstrated that
this can be correlated with decreased virulence in animal models of sepsis and osteomyelitis. Moreover, we
have confirmed that all of these phenotypes are evident in diverse clinical isolates of S. aureus and that they
can be reversed by eliminating the ability of sarA mutants to produce extracellular proteases. In this proposal,
we will expand on these observations to identify the specific extracellular proteases that are most relevant in
the context of our underlying scientific hypothesis in diverse clinical isolates of S. aureus (Aim 1) and use the
information gained to interrogate the impact of these proteases on the virulence factor repertoire on these
clinical isolates, define the impact sarA and these proteases on bone remodeling and the host response in
bone infection, and ultimately identify and evaluate the contribution of specific S. aureus virulence factors alone
and in combination with each other on these phenotypes (Aim 2).
摘要 摘要
我们已经证明葡萄球菌中的葡萄球菌辅助调节(sarA)突变
金黄色葡萄球菌导致细胞外蛋白酶的产生增加到限制生物膜的程度
形成,限制哺乳动物细胞(包括成骨细胞和破骨细胞)的细胞毒性,并限制
表面相关毒力因子和细胞外毒力因子的积累。我们还证明了
这可能与败血症和骨髓炎动物模型中毒力的降低有关。此外,我们
已证实所有这些表型在金黄色葡萄球菌的不同临床分离株中都很明显,并且它们
可以通过消除 sarA 突变体产生细胞外蛋白酶的能力来逆转。在这个提案中,
我们将扩展这些观察结果,以确定与以下情况最相关的特定细胞外蛋白酶:
我们在金黄色葡萄球菌的不同临床分离株中的基本科学假设的背景(目标 1)并使用
获得的信息用于询问这些蛋白酶对毒力因子库的影响
临床分离,定义 sarA 和这些蛋白酶对骨重建和宿主反应的影响
骨感染,最终识别和评估特定金黄色葡萄球菌毒力因子的贡献
并在这些表型上相互结合(目标 2)。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MARK S SMELTZER其他文献
MARK S SMELTZER的其他文献
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{{ truncateString('MARK S SMELTZER', 18)}}的其他基金
Core A: Administrative and Scientific Development Core
核心A:行政和科学发展核心
- 批准号:
10618373 - 财政年份:2022
- 资助金额:
$ 45.2万 - 项目类别:
Center for Microbial Pathogenesis and Host Inflammatory Responses
微生物发病机制和宿主炎症反应中心
- 批准号:
10412838 - 财政年份:2022
- 资助金额:
$ 45.2万 - 项目类别:
Core A: Administrative and Scientific Development Core
核心A:行政和科学发展核心
- 批准号:
10412839 - 财政年份:2022
- 资助金额:
$ 45.2万 - 项目类别:
Center for Microbial Pathogenesis and Host Inflammatory Responses
微生物发病机制和宿主炎症反应中心
- 批准号:
10618372 - 财政年份:2022
- 资助金额:
$ 45.2万 - 项目类别:
Impact of Staphylococcus aureus in osteomyelitis and bone physiology
金黄色葡萄球菌对骨髓炎和骨生理学的影响
- 批准号:
9271859 - 财政年份:2015
- 资助金额:
$ 45.2万 - 项目类别:
Defining the role of post-translational regulation by extracellular proteases in the pathogenesis of Staphylococcus aureus osteomyelitis
确定细胞外蛋白酶翻译后调节在金黄色葡萄球菌骨髓炎发病机制中的作用
- 批准号:
10379698 - 财政年份:2015
- 资助金额:
$ 45.2万 - 项目类别:
Impact of Staphylococcus aureus in osteomyelitis and bone physiology
金黄色葡萄球菌对骨髓炎和骨生理学的影响
- 批准号:
8951509 - 财政年份:2015
- 资助金额:
$ 45.2万 - 项目类别:
Impact of Staphylococcus aureus in osteomyelitis and bone physiology
金黄色葡萄球菌对骨髓炎和骨生理学的影响
- 批准号:
9089872 - 财政年份:2015
- 资助金额:
$ 45.2万 - 项目类别:
Defining the role of post-translational regulation by extracellular proteases in the pathogenesis of Staphylococcus aureus osteomyelitis
确定细胞外蛋白酶翻译后调节在金黄色葡萄球菌骨髓炎发病机制中的作用
- 批准号:
10493318 - 财政年份:2015
- 资助金额:
$ 45.2万 - 项目类别:
Shared Resource to Investigate Cellular Metabolism
研究细胞代谢的共享资源
- 批准号:
10399842 - 财政年份:2012
- 资助金额:
$ 45.2万 - 项目类别:
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