Biomarkers of Chlamydial Susceptibility and Disease

衣原体敏感性和疾病的生物标志物

• 批准号: 10615100
• 负责人: CATHERINE MARY O'CONNELL
• 金额: $ 83.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615100
• 关键词: 16S ribosomal RNA sequencing; Acceleration; Acute; Automobile Driving; Biological Markers; Blood; Cervical; Cervix Uteri; Characteristics; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Clinical; Contraceptive Usage; DNA; Data; Diagnosis; Diagnostic Sensitivity; Disease; Disease Pathway; Ectopic Pregnancy; Endometritis; Evaluation; Exposure to; Focal Infection; Gene Chips; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Markers; Genotype; Goals; High Risk Woman; Human; Immune; Immune response; Immunity; Immunization; Individual; Infection; Infertility; Inflammatory; Inflammatory Response; Knowledge; Lead; Link; Maps; Measures; Mediation; Messenger RNA; Modeling; Molecular; Monitor; North Carolina; Oral Contraceptives; Outcome; Participant; Pathology; Pathway Analysis; Pathway interactions; Pelvic Inflammatory Disease; Population; Predisposition; Prevention; Preventive vaccine; Process; Quantitative Trait Loci; Reproductive Health; Research; Research Design; Resolution; Risk; SNP array; Source; Surrogate Endpoint; Testing; Translating; Treatment Efficacy; United States National Institutes of Health; Universities; Vaccine Design; Vaccines; Woman; Women' s Health; Work; adaptive immune response; biomarker identification; biomarker panel; candidate marker; causal variant; cervicovaginal microbiome; chlamydia vaccine; chronic pelvic pain; clinically relevant; co-infection; cohort; cost; disease phenotype; disorder risk; genome-wide; hormonal contraception; improved; innovation; long-term sequelae; molecular marker; novel therapeutics; pathogen; prevent; programs; recruit; reproductive; reproductive morbidity; reproductive tract; response; risk prediction; transcriptomics; transmission process; vaccine development; vaccine efficacy; vaccine evaluation; vaccine trial; vaginal microbiota; working group

In a subset of Chlamydia trachomatis-infected women, the infection escapes immune control and ascends to the upper reproductive tract. There is a fundamental gap in understanding how pathways activated by chlamydial infection lead to immune pathology and reproductive morbidity in women. Its continued existence is a significant barrier to identification of biomarkers to diagnose or predict risk for reproductive sequelae after exposure. The long-term goal of this program is to develop vaccines that reduce transmission and prevent reproductive tract sequelae after exposure to C. trachomatis. The overall objective of this proposal is to identify biomarkers of asymptomatic ascending infection and endometritis in women and genetic biomarkers of susceptibility/risk for disease. The central hypothesis is that protective and immunopathologic responses elicited in response to STI associate with characteristic transcriptional signatures and genetic variance. The rationale for this project is that identifying biomarkers of susceptibility to ascending infection and risk for subsequent immune pathology will accelerate rational vaccine design and testing by (i) identifying individuals most likely to benefit from immunization, to facilitate appropriately powered studies, (ii) enabling balanced group selection for vaccine trials, and (iii) serving as clinical measures of vaccine efficacy. Blood-borne transcriptional profiling of women with a spectrum of chlamydial genital tract infection revealed specific inflammatory pathways associated with disease and enabled definition of a biomarker panel that diagnoses endometritis in asymptomatically-infected women with high chlamydial burden. Guided by strong preliminary data, the following three specific aims will test the hypothesis: 1) Determine candidate biomarkers positively- or negatively associated with ascending chlamydial infection in asymptomatic women; 2) Identify genetic biomarkers of susceptibility to ascending chlamydial infection and risk for subsequent reproductive sequelae; and 3) Identify disease-causing pathways and their key regulators engaged during ascending chlamydial infection, using causal network analysis. The first aim will profile cervical inflammatory responses from women with local infection or upper tract involvement in a new cohort of highly-exposed women (TRAC2, Core B). Pathogen load, co-infection, cervicovaginal microbiome and hormonal contraceptives will be assessed as confounders or additional biomarkers. The remaining aims will focus on integrating genotype, gene expression and disease phenotypes from TRAC2 and previously-profiled cohorts via expression quantitative trait locus (eQTL) mapping and causal mediation test, and on identification of disease- causal genes, using graphical models. The research proposed is innovative, in our opinion, because it will implement a comprehensive, non-biased approach to the identification of molecular biomarkers in a highly disease-relevant clinical population. The proposed research is significant because it is expected to translate directly to anti-chlamydial vaccine evaluation in humans and to have broad importance for diagnosis and for evaluation of novel therapeutics.

在一部分沙眼衣原体感染的妇女中，感染逃脱了免疫控制，并上升到 上生殖道在理解衣原体如何激活途径方面存在根本性的差距 感染导致妇女免疫病理和生殖疾病。它的继续存在是一个重要的 识别生物标志物以诊断或预测暴露后生殖后遗症风险的障碍。的 该计划的长期目标是开发减少传播和预防生殖道感染的疫苗 暴露于C.沙眼该提案的总体目标是确定以下生物标志物： 女性无症状上行性感染和尿道炎以及易感性/风险的遗传生物标志物 疾病中心假设是，保护性和免疫病理反应引起的回应STI 与特征转录签名和遗传变异相关。该项目的基本原理是， 鉴定对上行感染的易感性和随后免疫病理学风险的生物标志物将 加速合理的疫苗设计和测试，方法是：（i）确定最有可能受益于 免疫接种，以促进适当的动力研究，（ii）使疫苗试验的平衡组选择， 和（iii）用作疫苗效力的临床测量。女性乳腺癌患者的血源性转录谱分析 衣原体生殖道感染谱揭示了与疾病相关的特异性炎症途径 并能够定义诊断无症状感染妇女的尿道炎的生物标志物组 衣原体感染率很高在强有力的初步数据的指导下，以下三个具体目标将检验 假设：1）确定与上行衣原体阳性或阴性相关的候选生物标志物 无症状妇女感染; 2）确定对上行衣原体易感性的遗传生物标志物 感染和随后生殖后遗症的风险;和3）确定致病途径及其关键 使用因果网络分析，在上行衣原体感染过程中参与调节。第一个目标是 在一个新的队列研究中，局部感染或上尿路受累的妇女的宫颈炎性反应， 高度暴露妇女（TRAC2，核心B）。病原体载量、合并感染、宫颈阴道微生物组和激素 避孕药将作为混杂因素或其他生物标志物进行评估。其余的目标将集中在 整合来自TRAC2和先前分析的队列的基因型、基因表达和疾病表型， 表达数量性状基因座（eQTL）定位和因果介导测试，以及对疾病的鉴定- 因果基因，使用图形模型。我们认为，这项研究是创新的，因为它将 实施一种全面的，无偏见的方法来识别分子生物标志物， 疾病相关临床人群。拟议的研究是重要的，因为它有望转化为 直接用于人类抗衣原体疫苗评估，并对诊断和治疗具有广泛的重要性 新疗法的评价。