Mechanism Underlying Nitrite Sensitivity of Mucoid Pseudomonas in COPD
COPD 中粘液假单胞菌亚硝酸盐敏感性的机制
基本信息
- 批准号:8391607
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-10-01 至 2013-09-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdverse effectsAerobicAffectAlginatesAnabolismAnimal ModelAnimalsBacteriaBathingBiochemistryBiological ModelsBloodCaringCell DeathCellsCerebrospinal FluidChronicChronic BronchitisChronic Obstructive Airway DiseaseClinical TrialsCommunitiesComplexDiagnosisDyspneaExpenditureExposure toGenesGeneticGenetic TranscriptionGoalsGrowthHealth Care CostsHospitalizationHospitalsHumanIn VitroInfectionJournalsKineticsLibrariesLiquid substanceLungLung diseasesMediatingMicrobial BiofilmsModelingMolecularMorbidity - disease rateMucous body substanceMusMutationNBL1 geneNitric OxideNitritesOpportunistic InfectionsOrganismPaperPatientsPatternPlayPrevalenceProtein SProteinsPseudomonasPseudomonas aeruginosaPublishingPulmonary EmphysemaRelative (related person)ResistanceRoleSigma FactorSiteSodium NitriteSystemTestingThickUrinary tractairway epitheliumairway surface liquidbasebronchial epitheliumcystic fibrosis airwaydesignimprovedin vivokillingsmembermortalitymouse modelmucoidmutantnovelpublic health relevanceresearch studyrespiratory
项目摘要
DESCRIPTION (provided by applicant):
Nearly 40% of Cincinnati VA patients suffer from chronic obstructive pulmonary disease (COPD) that often suffer from airway infection by opportunistic bacteria, the most prevalent of which is Pseudomonas aeruginosa (PA). PA is found at high titers in chronically infected COPD airways and many strains are mucoid, resulting from overproduction of a viscous exopolysaccharide called alginate. The major mechanism of mucoid conversion of PA is via mutations. These mutations occur predominantly (>84-92%) within mucA, encoding an anti-sigma factor. Without MucA, the sigma factor AlgT(U) directs transcription of genes involved in alginate biosynthesis, resulting in mucoidy. In 2006, we published a paper in the Journal of Clinical Investigation, demonstrating that mucoid mucA mutant bacteria are killed during anaerobic exposure to acidified nitrite (A- NO2-). However, inactivation of algT(U) in the mucA background did not relieve sensitivity to acicified nitrite strongly indicating the affects observed were MucA-specific. Provision of mucA in trans restored A-NO2- resistance and subsequent experiments established that nitric oxide (NO) plays a role in cell death. Importantly, no adverse effects were observed when A-NO2- was applied to human airway epithelia. In summary, we have discovered a novel, non-toxic agent that could potentially achieve the translational goal of eradicating mucoid PA from the airways of COPD patients. Three specific aims are proposed and designed to determine (i) the mechanism(s) underlying A-NO2- sensitivity in mucA mutant bacteria, (ii) the role of MucA and members of the anaerobic respiratory cascade in biofilm sensitivity to A-NO2-, and (iii) to test the hypothesis that mucA and double anaerobic regulator mutants will be even more sensitive to A-NO2- in a tried-and-true mouse model of chronic lung infection. Aim 1. Identify the molecular basis underlying anaerobic acidified NO2- sensitivity in mucoid mucA mutant PA. Although our discovery in 2006 describes an "Achilles' Heel" of mucoid, mucA mutant bacteria, we still do not know the mechanism of killing of these organisms by A-NO2-. Specifically, the role of MucA, NO3-/NO2- transport, anaerobic regulatory machinery and NO-sensitive sulfhydryl/Fe-containing proteins is very much underappreciated. The molecular basis will be determined by (i) micoarray studies of mucA and wild-type strains grown under aerobic and anaerobic conditions; (ii) determination of the cellular MucA levels that allow nitrite sensitivity, (iii) determining the rates/levels of NO2- and NO3- transport in mucA and WT and mucA double (anaerobic regulatory hierarchy genes) and; (iv) elucidate the status of critical cellular proteins known to be targets of nitrosylation. Aim 2. Determine the effects of NO2- on viability of wild-type versus mucoid, DmucA mutants in complex, highly organized communities known as biofilms using 3 different established model systems. The biofilm mode of growth is that which has been determined to exist and actually thrive within the thick CF airway mucus. We will use 3 complimentary yet contrasting approaches that include (i) a static biofilm system, representing the stagnant mucus of COPD airways, (ii) a flow-through system that represents a contrasting biofilm mode of growth, and finally (iii) growth is static biofilms in airway surface liquid derived from human primary cells. Aim 3. Determine the effects of NO2- on viability of wild-type versus DmucA and double mucA anaerobic regulatory mutants in an established murine chronic lung infection model. Proof-of-principle animal studies are required to show the relative efficacy of the aforementioned treatments on not only mucA mutant organisms, but also mucA mutants with selected second site mutations in genes encoding proteins that are S-nitrosylated upon exposure to A-NO2-.
描述(由申请人提供):
项目成果
期刊论文数量(1)
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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DANIEL J. HASSETT其他文献
DANIEL J. HASSETT的其他文献
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{{ truncateString('DANIEL J. HASSETT', 18)}}的其他基金
Mechanism Underlying Nitrite Sensitivity of Mucoid Pseudomonas in COPD
COPD 中粘液假单胞菌亚硝酸盐敏感性的机制
- 批准号:
7931027 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Mechanism Underlying Nitrite Sensitivity of Mucoid Pseudomonas in COPD
COPD 中粘液假单胞菌亚硝酸盐敏感性的机制
- 批准号:
8196343 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Role of OxyR in P. aeruginosa Biofilm Resistance to H202
OxyR 在铜绿假单胞菌生物膜 H2O2 抗性中的作用
- 批准号:
7271227 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Role of OxyR in P. aeruginosa Biofilm Resistance to H202
OxyR 在铜绿假单胞菌生物膜 H2O2 抗性中的作用
- 批准号:
6831086 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Role of OxyR in P. aeruginosa Biofilm Resistance to H202
OxyR 在铜绿假单胞菌生物膜 H2O2 抗性中的作用
- 批准号:
6931186 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Role of OxyR in P. aeruginosa Biofilm Resistance to H202
OxyR 在铜绿假单胞菌生物膜 H2O2 抗性中的作用
- 批准号:
7111811 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Proteogenome of Anaerobic P. aeruginosa in CF Mucus
CF 粘液中厌氧铜绿假单胞菌的蛋白质组
- 批准号:
6609992 - 财政年份:2003
- 资助金额:
-- - 项目类别:
B.pseudomallei bioterrorism and quorum sensing
B.pseudomallei 生物恐怖主义和群体感应
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6659914 - 财政年份:2002
- 资助金额:
-- - 项目类别:
B.pseudomallei bioterrorism and quorum sensing
B.pseudomallei 生物恐怖主义和群体感应
- 批准号:
6556955 - 财政年份:2002
- 资助金额:
-- - 项目类别:
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