Regulation of Ps. aeruginosa Virulence Factors by AlgR
诗篇的规定。
基本信息
- 批准号:7385989
- 负责人:
- 金额:$ 25.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-02-01 至 2010-01-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAffinityAlginatesAnabolismAntibiotic ResistanceApoptosisAspartateAspergillus Nuclease S1BacteremiaBacteriaBindingBinding SitesBiological AssayBiologyBurn injuryCellsChronicCommitConditionCystic FibrosisDNA-Protein InteractionDNase-I FootprintingDataDermatitisElectron TransportEnzymesEpithelialEpithelial CellsEukaryotic CellGene ExpressionGenesGenetic TranscriptionGoalsGrowthHumanHydrogen CyanideImmuneIn VitroIndividualInfectionLacZ GenesLungMalignant NeoplasmsMeasurementMeasuresMediatingMetabolismMicrobial BiofilmsModelingMorbidity - disease rateNecrosisNuclease Protection AssaysOrganismPathogenesisPatientsPeroxidasePeroxidasesPhosphoric Monoester HydrolasesPhosphorylationPhosphorylation SitePhosphotransferasesPilumPlayPoisoningProcessProcess MeasureProductionPseudomonasPseudomonas InfectionsPseudomonas aeruginosaRegulationRegulonRelative (related person)Respiratory SystemRespiratory tract structureRoleSepticemiaSite-Directed MutagenesisSoft Tissue InfectionsStagingSuperoxide DismutaseTestingTherapeuticTimeTissue TransplantationTranscription CoactivatorTransplant RecipientsUrinary tractVirulenceVirulence Factorscatalasecell killingcell motilitycystic fibrosis patientsgel mobility shift assayhydrogen cyanide synthaseimprovedmetalloenzymemortalitymucoidmutantneutrophilnitrogen metabolismnovel strategiesnucleasepathogenpromoterrespiratoryrhamnolipidtherapeutic target
项目摘要
DESCRIPTION (provided by applicant): Pseudomonas aeruginosa is ubiquitous, opportunistic pathogen that primarily infects immune-compromised individuals, including AIDS and transplant patients, severe burn patients, and those with cystic fibrosis (CF). In the context of CF, P. aeruginosa establishes a chronic condition whose morbidity and mortality results from lung damage. Due to the uncanny antibiotic resistance, CF patients infected with Pseudomonas often have chronic infections with limited therapeutic options. Therefore, for improved efficacy in treatment, a basic understanding of the pathogenic mechanisms utilized by this organism needs to be examined as possible therapeutic targets. While a majority of previous studies have focused on the initial stages of colonization and infection, we propose a new approach in searching for treatments. Mounting evidence indicates that microaerophilic metabolism and a biofilm mode of growth may be involved in P. aeruginosa pathogenesis; however, explanations for a mechanism have yet to be discussed. One virulence factor produced by P. aeruginosa under these growth conditions is HCN. Micromolar amounts of HCN inhibit the respiratory electron transport chain and several metalloenzymes (e.g., catalase, peroxidase, superoxide dismutase) of eukaryotic cells. We have discovered that AlgR, a regulator of the virulence factor, alginate, also activates HCN production in mucoid P. aeruginosa. Using the Pseudomonas Affymetrix GeneChip and S1 nuclease protection assays, we demonstrate that AlgR is controlling hcnA, encoding hydrogen cyanide synthase. Moreover, direct measurement of HCN production revealed that mucoid P. aeruginosa produce up to 2.5 mM of HCN in 4 h. Our preliminary data indicate two new roles for AlgR: i) AlgR controls HCN production and ii) AlgR is able to switch from a repressor in nonmcoid P. aeruginosa to an activator in mucoid bacteria on the hcnA promoter. Additionally, we demonstrate that AlgZ/FimS is playing a role in this process. The hypothesis to be tested is: AlgR activates HCN production in mucoid P. aeruginosa. We will test this hypothesis with four specific aims: i) we will determine the requirements for AlgR protein-DNA interaction within the hcnA promoter; ii) we will determine if phosphorylation is required for AlgR activation of hcnA expression in mucoid P. aeruginosa; iii) we will determine the amount of HCN production and hcnA expression within biofilms, and; iv) we will determine the effect of HCN production on lung epithelial and human neutrophil cells in vitro. Thus, at the end of our proposed studies, we hope to elucidate new possible therapeutic target as well as gaining a better understanding of Pseudomonas biology and pathogenesis.
描述(由申请方提供):铜绿假单胞菌是一种普遍存在的机会致病菌,主要感染免疫功能低下的个体,包括艾滋病和移植患者、严重烧伤患者和囊性纤维化(CF)患者。在CF的背景下,铜绿假单胞菌建立了一种慢性病症,其发病率和死亡率由肺损伤引起。由于不可思议的抗生素耐药性,感染假单胞菌的CF患者通常患有慢性感染,治疗选择有限。因此,为了提高治疗效果,需要对这种生物体所利用的致病机制进行基本了解,作为可能的治疗靶点。虽然大多数以前的研究都集中在殖民和感染的初始阶段,我们提出了一种新的方法来寻找治疗。越来越多的证据表明,微需氧代谢和生物膜生长模式可能参与铜绿假单胞菌的发病机制;然而,对机制的解释还有待讨论。由铜绿假单胞菌在这些生长条件下产生的一种毒力因子是HCN。微摩尔量的HCN抑制呼吸电子传递链和几种金属酶(例如,过氧化氢酶、过氧化物酶、超氧化物歧化酶)。我们已经发现,AlgR,一种毒力因子藻酸盐的调节剂,也激活粘液铜绿假单胞菌中HCN的产生。使用假单胞菌亲和基因芯片和S1核酸酶保护试验,我们证明,AlgR控制hcnA,编码氰化氢合酶。此外,HCN产生的直接测量显示粘液样铜绿假单胞菌在4小时内产生高达2.5mM的HCN。我们的初步数据表明AlgR的两个新作用:i)AlgR控制HCN产生和ii)AlgR能够在hcnA启动子上从非粘液铜绿假单胞菌中的阻遏物转换为粘液细菌中的激活物。此外,我们证明了AlgZ/FimS在这个过程中发挥了作用。待检验的假设是:AlgR激活粘液样铜绿假单胞菌中的HCN产生。我们将用四个具体目标来检验这一假设:i)我们将确定hcnA启动子内AlgR蛋白-DNA相互作用的要求; ii)我们将确定粘液样铜绿假单胞菌中hcnA表达的AlgR激活是否需要磷酸化; iii)我们将确定生物膜内HCN产生和hcnA表达的量;以及; iv)我们将在体外确定HCN产生对肺上皮细胞和人中性粒细胞的影响。因此,在我们提出的研究结束时,我们希望阐明新的可能的治疗靶点,以及获得更好的理解假单胞菌的生物学和发病机制。
项目成果
期刊论文数量(6)
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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Michael John Schurr其他文献
Nutrition and Wound Healing, 1st Edition
- DOI:
10.1016/j.jamcollsurg.2007.11.003 - 发表时间:
2008-03-01 - 期刊:
- 影响因子:
- 作者:
Michael John Schurr - 通讯作者:
Michael John Schurr
Michael John Schurr的其他文献
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{{ truncateString('Michael John Schurr', 18)}}的其他基金
Targeted Nanogel based Therapies for Chronic Recurrent Urinary Tract Infections
基于纳米凝胶的靶向治疗慢性复发性尿路感染
- 批准号:
10186703 - 财政年份:2020
- 资助金额:
$ 25.07万 - 项目类别:
Control of Pseudomonas aeruginosa Quorum Sensing and Alginate
铜绿假单胞菌群体感应和藻酸盐的控制
- 批准号:
8449575 - 财政年份:2012
- 资助金额:
$ 25.07万 - 项目类别:
Control of Pseudomonas aeruginosa Quorum Sensing and Alginate
铜绿假单胞菌群体感应和藻酸盐的控制
- 批准号:
8240832 - 财政年份:2012
- 资助金额:
$ 25.07万 - 项目类别:
LOCAL ANESTHETIC INFUSION FOR PAIN MANAGEMENT FOLLOWING INGUINAL HERNIA REPAIR
腹股沟疝气修复术后局部麻醉输注治疗疼痛
- 批准号:
7204325 - 财政年份:2005
- 资助金额:
$ 25.07万 - 项目类别:
Regulation of Ps. aeruginosa Virulence Factors by AlgR
诗篇的规定。
- 批准号:
6846055 - 财政年份:2004
- 资助金额:
$ 25.07万 - 项目类别:
Regulation of Ps. aeruginosa Virulence Factors by AlgR
诗篇的规定。
- 批准号:
7171785 - 财政年份:2004
- 资助金额:
$ 25.07万 - 项目类别:
Regulation of Ps. aeruginosa Virulence Factors by AlgR
诗篇的规定。
- 批准号:
6777853 - 财政年份:2004
- 资助金额:
$ 25.07万 - 项目类别:
Regulation of Ps. aeruginosa Virulence Factors by AlgR
诗篇的规定。
- 批准号:
7340222 - 财政年份:2004
- 资助金额:
$ 25.07万 - 项目类别:
Regulation of Ps. aeruginosa Virulence Factors by AlgR
诗篇的规定。
- 批准号:
7008891 - 财政年份:2004
- 资助金额:
$ 25.07万 - 项目类别:
Local Anesthetic Infusion for Pain Management Following Inguinal Hernia Repair
局部麻醉输注用于腹股沟疝修补术后疼痛管理
- 批准号:
7043863 - 财政年份:2003
- 资助金额:
$ 25.07万 - 项目类别:
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