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

• 批准号: 10629735
• 负责人: YUSUF OSEOBHUNU OMOSUN
• 金额: $ 14.2万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10629735
• 关键词: ARNTL gene; Affect; African Trypanosomiasis; Bacterial Sexually Transmitted Diseases; Biological Markers; Cells; Chlamydia; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Circadian Dysregulation; Circadian Rhythms; Contracts; Darkness; Development; Disease; Disease Outcome; Feedback; Fertility; Fibrosis; Genes; Genetic; Genetic Transcription; Goals; Hour; Human Herpesvirus 2; Infection; Infertility; Inflammation; Inflammatory Response; Influenza; Jet Lag Syndrome; Knockout Mice; Knowledge; Malaria; Mediating; MicroRNAs; Mission; Modeling; Molecular; Mus; Ontology; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Pelvic Inflammatory Disease; Periodicity; Physiological; Physiology; Predisposition; Principal Investigator; Proteins; Public Health; Reporting; Repression; Reproductive Health; Research; Rest; Role; Salmonella typhimurium; Salpingitis; Severities; Sleep Disorders; Symptoms; Technology; Testing; Time; United States; United States National Institutes of Health; Variant; Woman; Work; circadian; circadian pacemaker; cryptochrome; differential expression; endometriosis; experimental study; innovation; insight; nano-string; novel; pathogen; programs; reproductive tract; response; transcription factor; transcriptomics; tubal infertility

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.

女性衣原体发病机制的表现之一是输卵管因素不孕（TFI）。分子 导致 TFI 的病理变化的机制尚不清楚。我们曾报道过 一天中的感染时间影响衣原体的传染性和发病机制。我们实验室的结果表明 当使用时差模型扰乱昼夜节律时，感染衣原体的小鼠的传染性增加 和病理学。我们的工作表明，与昼夜节律相关的 miRNA 和基因 衣原体感染期间差异表达。我们在这项研究中的前提假设昼夜节律 在控制/调节衣原体发病机制中发挥作用，导致不孕。该项目的中心目标 是通过这些目标了解昼夜节律对衣原体发病机制的作用 (1) 调查 宿主昼夜节律与衣原体发病机制的关联。我们假设昼夜节律控制 衣原体发病机制对于确定疾病结果至关重要。我们将确定角色和 使用市售时钟基因 Bmal1、Per2 和 Cry1 参与衣原体发病机制 Bmal1KO、Per2KO 和 Cry1KO 小鼠。 (2) 定义衣原体参与途径的昼夜节律控制 发病。我们假设生殖道对致病变化的内在倾向将 取决于时钟基因激活或抑制哪些基因/蛋白质。我们还将确定基因 在不同的衣原体感染状态下进行循环。我们将使用 C. muridarum 来检验这个假设 感染 WT、Bmal1KO、Per2KO 和 Cry1KO 小鼠。这项研究为我们预测严重程度提供了基础 衣原体感染后的发病机制并确定衣原体涉及的新的潜在机制 发病。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。