Metabolic regulation in otitis media
中耳炎的代谢调节
基本信息
- 批准号:7885448
- 负责人:
- 金额:$ 33.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-09 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAirAllelesAntibiotic TherapyAntibioticsAntitoxinsAttenuatedBindingBiochemicalBiological AssayBiological ModelsCell CycleChildChinchilla (genus)ChronicChronic DiseaseClinicalComplexDataDiseaseEnvironmentExhibitsFactor For Inversion Stimulation ProteinFailureGene FamilyGenesGeneticGrowthHaemophilus influenzae type b bacteriaHistologyHumanIn VitroInfectionInterventionLanguage DevelopmentLeadLifeLiquid substanceMeasuresMediatingMetabolicMicrobial BiofilmsModelingMolecularMucous MembraneMutateNontypable Haemophilus influenzaNutrientOperonOrganismOtitis MediaParasitesParentsPathogenesisPathway interactionsPatientsPeptide HydrolasesPharmacologic SubstancePhenotypePlasmidsPromoter RegionsProteinsPublic HealthRecurrenceRegulationRelative (related person)Replication OriginResearchRibonucleasesStressTestingTimeTissue ModelTissuesToxinTranscriptional RegulationTransmission Electron MicroscopyTreatment FailureUpper respiratory tractVaccinesantimicrobialclinically significantdeafnessear infectionhuman tissueimprovedin vivomiddle earmutantnew therapeutic targetnovelnucleasepromoterprotein complexpublic health relevance
项目摘要
DESCRIPTION (provided by applicant): Nonencapsulated (nontypeable) Haemophilus influenzae (NTHi) are human-adapted commensal organisms that can also cause chronic mucosal infections, particularly otitis media. Since NTHi are not susceptible to the routinely-administered Hib vaccine, these infections are usually treated with antibiotics. Many children exhibit recurrent otitis media caused by NTHi despite antibiotic treatment, and these episodes can lead to deafness and language development delays in early life. Although the ability to form biofilms has been implicated in persistent infections, the exact molecular mechanism by which NTHi causes chronic disease is not fully understood. NTHi contain a set of four highly conserved gene pairs termed toxin-antitoxin (TA) loci. Our preliminary data shows that the deletion of two of these gene pairs significantly reduces the ability of the organism to cause long-term infections in a primary human tissue model. Our hypothesis is that these four TA loci are involved in protease-mediated metabolic regulation that allows the organism to enter a state of growth arrest precipitated by stress (such as antibiotic therapy or nutrient limitation), and this enhances their ability to survive under these suboptimal conditions. Once conditions improve (e.g. cessation of antibiotic treatment, or nutrient upshift), bacterial growth resumes. Since most antibiotics target essential biosynthetic pathways that are not utilized during growth arrest, this mechanism could explain the observed clinical failure in children with recurrent otitis media, and result in new targets for the treatment of chronic infections. To investigate this, we aim to a) progressively delete all four TA loci from two different NTHi strains; b) assess the ability of these mutants to survive in long-term infections of a primary human tissue model grown at the air-liquid interface, and c) analyze the mutants that were found to be significantly attenuated for persistence in the chinchilla model of otitis media. Because TA loci appear in hundreds of different bacterial species, in addition to discovering novel targets for immunological or pharmacological intervention for those patients that exhibit chronic disease, these studies have implications for the treatment of many other organisms that persist within a host or in the environment. PUBLIC HEALTH RELEVANCE: antibiotic treatment failure in children that results in recurrent middle ear infections (otitis media). These episodes can lead to deafness as well as language development delays. Our research could lead to the identification of new targets for vaccines or pharmaceuticals that would synergize with existing treatments for those patients that exhibit chronic otitis media.
描述(由申请人提供):非封装(不可分型)流感嗜血杆菌(NTHi)是适应人类的共生生物,也可引起慢性粘膜感染,特别是中耳炎。由于 NTHi 对常规接种的 Hib 疫苗不敏感,因此这些感染通常用抗生素治疗。尽管进行了抗生素治疗,许多儿童仍会出现由 NTHi 引起的复发性中耳炎,这些发作可能会导致早年耳聋和语言发育迟缓。尽管形成生物膜的能力与持续感染有关,但 NTHi 引起慢性疾病的确切分子机制尚不完全清楚。 NTHi 包含一组四个高度保守的基因对,称为毒素-抗毒素 (TA) 位点。我们的初步数据表明,删除其中两个基因对会显着降低生物体在原代人体组织模型中引起长期感染的能力。我们的假设是,这四个 TA 基因座参与蛋白酶介导的代谢调节,使生物体进入由应激(例如抗生素治疗或营养限制)引发的生长停滞状态,这增强了它们在这些次优条件下的生存能力。状况。一旦情况改善(例如停止抗生素治疗或营养物质增加),细菌就会恢复生长。由于大多数抗生素针对生长停滞期间未利用的重要生物合成途径,因此这种机制可以解释在患有复发性中耳炎的儿童中观察到的临床失败,并为治疗慢性感染提供新的目标。为了研究这一点,我们的目标是 a) 逐步删除两个不同 NTHi 菌株的所有四个 TA 位点; b) 评估这些突变体在气液界面生长的原代人体组织模型的长期感染中存活的能力,以及 c) 分析发现在龙猫中耳炎模型中持久性显着减弱的突变体媒体。由于 TA 基因座出现在数百种不同的细菌物种中,除了为那些表现出慢性疾病的患者发现免疫学或药物干预的新靶标之外,这些研究对于治疗宿主或环境中持续存在的许多其他生物体也具有重要意义。公共卫生相关性:儿童抗生素治疗失败导致复发性中耳感染(中耳炎)。这些事件可能导致耳聋以及语言发育迟缓。我们的研究可能会确定疫苗或药物的新靶标,这些靶标将与针对患有慢性中耳炎的患者的现有治疗方法产生协同作用。
项目成果
期刊论文数量(0)
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Dayle Anita Daines其他文献
Dayle Anita Daines的其他文献
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{{ truncateString('Dayle Anita Daines', 18)}}的其他基金
High Throughput Screening to Discover Novel Toxin Inhibitors Relevant to the Treatment of Otitis Media
高通量筛选发现与中耳炎治疗相关的新型毒素抑制剂
- 批准号:
9310342 - 财政年份:2015
- 资助金额:
$ 33.38万 - 项目类别:
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