Determining the role of circadian rhythms in Chlamydia associated tubal infertility
确定昼夜节律在衣原体相关输卵管不孕症中的作用
基本信息
- 批准号:10629735
- 负责人:
- 金额:$ 14.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-24 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:ARNTL geneAffectAfrican TrypanosomiasisBacterial Sexually Transmitted DiseasesBiological MarkersCellsChlamydiaChlamydia InfectionsChlamydia muridarumChlamydia trachomatisCircadian DysregulationCircadian RhythmsContractsDarknessDevelopmentDiseaseDisease OutcomeFeedbackFertilityFibrosisGenesGeneticGenetic TranscriptionGoalsHourHuman Herpesvirus 2InfectionInfertilityInflammationInflammatory ResponseInfluenzaJet Lag SyndromeKnockout MiceKnowledgeMalariaMediatingMicroRNAsMissionModelingMolecularMusOntologyOutcomePathogenesisPathogenicityPathologicPathologyPathway interactionsPelvic Inflammatory DiseasePeriodicityPhysiologicalPhysiologyPredispositionPrincipal InvestigatorProteinsPublic HealthReportingRepressionReproductive HealthResearchRestRoleSalmonella typhimuriumSalpingitisSeveritiesSleep DisordersSymptomsTechnologyTestingTimeUnited StatesUnited States National Institutes of HealthVariantWomanWorkcircadiancircadian pacemakercryptochromedifferential expressionendometriosisexperimental studyinnovationinsightnano-stringnovelpathogenprogramsreproductive tractresponsetranscription factortranscriptomicstubal infertility
项目摘要
One of the manifestations of Chlamydial pathogenesis in women is tubal factor infertility (TFI). The molecular
mechanism underpinning the pathologic changes that cause TFI is poorly understood. We have reported that
the time of day of infection influences chlamydia infectivity and pathogenesis. Results from our lab show that
when circadian rhythms were disrupted using a Jet lag model, chlamydia-infected mice had increased infectivity
and pathology. Our work has demonstrated that miRNAs and genes associated with circadian rhythms are
differentially expressed during chlamydia infection. Our premise in this study hypothesizes that circadian rhythms
have a role in controlling/regulating chlamydial pathogenesis, leading to infertility. The central goal of this project
is to understand the role of circadian rhythms on chlamydial pathogenesis through these aims (1) Investigate the
association of host circadian rhythms with chlamydial pathogenesis. We hypothesize that circadian control of
chlamydial pathogenesis is essential in determining disease outcomes. We will determine the role and
involvement of clock genes Bmal1, Per2, and Cry1 on chlamydial pathogenesis using commercially available
Bmal1KO, Per2KO, and Cry1KO mice. (2) Define the circadian control of pathways involved in chlamydial
pathogenesis. We hypothesize that the intrinsic disposition of the genital tract to pathogeneic changes will
depend on what genes/proteins are activated or inhibited by clock genes. We will also determine genes that are
undergoing cycling at different states of chlamydia infection. We will test this hypothesis using C. muridarum
infected WT, Bmal1KO, Per2KO, and Cry1KO mice. This study gives us a basis to predict the level of severity
of pathogenesis after chlamydia infection and identify new underlying mechanisms involved in chlamydia
pathogenesis. By accomplishing the outcomes of the specific aims, we predict that the knowledge gained will
positively impact women's reproductive health.
女性衣原体致病的表现之一是输卵管因素不孕症(TFI)。分子
导致TFI的病理变化的机制尚不清楚。我们已经报道了
感染的时间影响衣原体的传染性和发病机理。我们实验室的结果显示,
当使用时差模型扰乱昼夜节律时,衣原体感染的小鼠的传染性增加,
和病理我们的工作已经证明,与昼夜节律相关的miRNA和基因,
在衣原体感染期间差异表达。我们在这项研究中假设昼夜节律
在控制/调节衣原体发病机制中起作用,导致不育。这个项目的中心目标
通过以下目的了解昼夜节律在衣原体发病机制中的作用:(1)研究衣原体感染的昼夜节律,
宿主昼夜节律与衣原体发病机制的关系。我们假设,
衣原体的发病机制是决定疾病结果的关键。我们将确定角色,
利用商业上可获得的生物钟基因Bmal 1、Per 2和Cry 1参与衣原体的发病机制
Bmal 1 KO、Per 2KO和Cry 1 KO小鼠。(2)定义衣原体感染相关通路的昼夜节律控制
发病机制我们假设生殖道对致病性变化的内在倾向将
这取决于哪些基因/蛋白质被生物钟基因激活或抑制。我们还将确定基因,
在不同的衣原体感染状态下循环。我们将使用C来测试这个假设。穆里达鲁姆
感染的WT、Bmal 1 KO、Per 2KO和Cry 1 KO小鼠。这项研究为我们预测严重程度提供了依据
衣原体感染后的发病机制,并确定新的潜在机制涉及衣原体
发病机制通过实现特定目标的结果,我们预测所获得的知识将
对妇女的生殖健康产生积极影响。
项目成果
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