Molecular Mechanisms of Type I IFN Induction during Chlamydia Infection
衣原体感染过程中 I 型干扰素诱导的分子机制
基本信息
- 批准号:8695757
- 负责人:
- 金额:$ 38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-06-03 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptor Signaling ProteinAffectAntibiotic TherapyAutomobile DrivingAvidityBindingBiological MarkersBlocking AntibodiesBloodCaspaseCaspase-1Cell DeathCervix UteriChlamydiaChlamydia InfectionsChlamydia trachomatisCyclic GMPDNADataDiagnosticDiseaseDisease susceptibilityEctopic PregnancyEndometriumEndoplasmic ReticulumEpithelial CellsEventFertilityFundingGenesGenital systemGoalsHMGB ProteinsHMGB1 geneHealthHumanIFNAR1 geneImmuneImmune responseInfectionInfertilityInfiltrationInflammationInflammatory ResponseInterferonsInterleukin-1Interleukin-1 ReceptorsInvestigationKnockout MiceLeadLigandsLinkMammalian OviductsMediatingMediator of activation proteinMethodsModelingMolecularMorbidity - disease rateMusOrgan Culture TechniquesOutcomePathologyPathway interactionsPatternPelvic Inflammatory DiseasePhysiologicalReceptor SignalingReproductive HealthResolutionRiskRoleSignal TransductionTestingTissuesWomanarmbaseclinically relevantcostgenetic variantgenital infectiongenital secretionhuman diseaseimprovedinhibitor/antagonistmouse modelnovel therapeuticsnovel vaccinespathogenpreventreceptorreceptor-mediated signalingreproductiveresponsesensortherapeutic targettool
项目摘要
DESCRIPTION (provided by applicant): Chlamydia trachomatis genital infection is a major cause of pelvic inflammatory disease (PID), resulting in ectopic pregnancy and infertility among women. PID is caused by an overt inflammatory response in the upper genital tract. The specific immune mechanisms and effectors that trigger this often-devastating condition are poorly defined. The mouse model is a useful tool to study these inflammatory responses in the oviduct. Using this model, we have shown that signaling from the host receptors IFNAR (IFNα/ß receptor) and IL-1R (IL-1 receptor) leads to oviduct pathology during genital chlamydial infection. However, the exact mechanisms by which chlamydiae initiate these responses, and the host molecules engaged, are unknown. The central hypothesis of this application is that type I IFN and IL-1 signaling synergistically drive oviduct damage during infection by activating cell death pathways and increasing PMN infiltration. Our overall objectives are to (1) delineate the upstream activators and downstream effectors of IFN and IL-1R signaling which lead to pathology, and (2) therapeutically block the downstream mediators of IL-1R signaling-induced oviduct damage, using the mouse model. To test our hypothesis and achieve our objectives, we will identify the specific molecular interaction between host DNA sensor and chlamydial effector that initiate IFNß expression during infection (Aim 1). We will test the hypothesis that caspase-11 mediated cell death activation is a major player in pathology and type I IFN signaling results in caspase-11 activation during infection (Aim 2). We will explore the role of damage associated molecular patterns (DAMPs), such as HMGB-1 and IL-1α present in genital secretions of infected mice, in oviduct pathology (Aim 3). We also propose to specifically target the damaging arm of IL-1R signaling using inhibitors in ex vivo Fallopian tube explants and in the mouse model to protect from pathology (Aim 4). The central theme of this application is that these signaling events likely evolved to reduce pathogen load in the oviduct, but lead to cell death and tissue damage, thereby come at an expense of adverse reproductive health in women. Delineating the innate immune pathways to segregate the damaging and protective constituents, facilitates therapeutic targeting to prevent disease without affecting resolution of infection. Specific outcomes of the proposed study include identification of host molecules involved in amplification of the inflammatory response during infection, which would serve as biomarkers and therapeutic targets to prevent reproductive sequelae in women infected with Chlamydia.
描述(申请人提供):沙眼衣原体生殖器感染是导致盆腔炎的主要原因,导致妇女异位妊娠和不孕。PID是由上生殖道的一种明显的炎症反应引起的。触发这种往往是毁灭性的疾病的特定免疫机制和效应器还没有明确的定义。小鼠模型是研究输卵管炎症反应的有用工具。利用该模型,我们发现在生殖道衣原体感染过程中,宿主受体IFNAR(干扰素α/B受体)和IL-1R(IL-1受体)的信号转导导致输卵管病变。然而,衣原体启动这些反应以及宿主分子参与的确切机制尚不清楚。这一应用的中心假设是,I型干扰素和IL-1信号在感染过程中通过激活细胞死亡途径和增加PMN渗透来协同驱动输卵管损伤。我们的总体目标是(1)描述导致病理的干扰素和IL-1R信号的上游激活因子和下游效应因子,以及(2)利用小鼠模型从治疗上阻断IL-1R信号诱导的输卵管损伤的下游介质。为了验证我们的假设并实现我们的目标,我们将确定宿主DNA传感器和衣原体效应器之间的特定分子相互作用,从而在感染过程中启动干扰素的表达(目标1)。我们将检验这一假设,即caspase-11介导的细胞死亡激活是病理中的主要参与者,而I型干扰素信号导致感染期间caspase-11激活(目标2)。我们将探索损伤相关分子模式(DAMP)在输卵管病理学中的作用(目标3),例如感染小鼠生殖器分泌物中存在的HMGB-1和IL-1α。我们还建议在体外输卵管外植体和小鼠模型中使用抑制剂来特异性地靶向IL-1R信号转导的损伤臂,以保护其免受病理影响(目标4)。这一应用的中心主题是,这些信号事件可能进化为减少输卵管中的病原体负载,但会导致细胞死亡和组织损伤,从而以损害女性的生殖健康为代价。描绘先天免疫途径以分离破坏性和保护性成分,有助于在不影响感染解决的情况下进行靶向治疗以预防疾病。这项拟议研究的具体结果包括确定感染期间炎症反应放大所涉及的宿主分子,这些分子将作为生物标记物和治疗目标,防止感染衣原体的妇女出现生殖后遗症。
项目成果
期刊论文数量(0)
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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Uma M Nagarajan其他文献
Uma M Nagarajan的其他文献
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{{ truncateString('Uma M Nagarajan', 18)}}的其他基金
IRF3 is a novel mediator of cell death during genital Chlamydia infection.
IRF3 是生殖器衣原体感染期间细胞死亡的新型介质。
- 批准号:
9092280 - 财政年份:2016
- 资助金额:
$ 38万 - 项目类别:
IRF3 is a novel mediator of cell death during genital Chlamydia infection.
IRF3 是生殖器衣原体感染期间细胞死亡的新型介质。
- 批准号:
9310325 - 财政年份:2016
- 资助金额:
$ 38万 - 项目类别:
Molecular Mechanisms of Type I IFN Induction during Chlamydia Infection
衣原体感染过程中 I 型干扰素诱导的分子机制
- 批准号:
8825397 - 财政年份:2007
- 资助金额:
$ 38万 - 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
- 批准号:
7876686 - 财政年份:2007
- 资助金额:
$ 38万 - 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
- 批准号:
8434975 - 财政年份:2007
- 资助金额:
$ 38万 - 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
- 批准号:
7627936 - 财政年份:2007
- 资助金额:
$ 38万 - 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
- 批准号:
7425070 - 财政年份:2007
- 资助金额:
$ 38万 - 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
- 批准号:
7263821 - 财政年份:2007
- 资助金额:
$ 38万 - 项目类别:
Molecular mechanisms of Chlamydia-induced Type 1 Interferon response
衣原体诱导 1 型干扰素反应的分子机制
- 批准号:
8067122 - 财政年份:2007
- 资助金额:
$ 38万 - 项目类别:
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