Biomarkers of Chlamydial Susceptibility and Disease

衣原体敏感性和疾病的生物标志物

基本信息

批准号：
10392975
负责人：
CATHERINE MARY O'CONNELL
金额：
$ 33.74万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10392975
关键词：
16S ribosomal RNA sequencing 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 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&apos 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 diagnosis evaluation disease phenotype disorder risk genome-wide hormonal contraception improved infection risk innovation long-term sequelae molecular marker novel therapeutics pathogen prevent programs recruit reproductive reproductive morbidity reproductive tract response transcriptomics transmission process vaccine development vaccine efficacy vaccine evaluation vaccine trial vaginal microbiota working group

项目摘要

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.

在感染沙眼衣原体的一部分中，感染逃脱了免疫控制并上升到上部生殖道。了解衣原体如何激活途径是有根本的差距感染导致女性的免疫病理和生殖发病率。它的持续存在是重要的鉴定生物标志物以诊断或预测暴露后繁殖后遗症风险的障碍。这该计划的长期目标是开发疫苗，以减少传播并防止生殖道暴露于沙眼梭状芽胞庭的后遗症。该提议的总体目的是确定女性的无症状升高感染和子宫内膜炎以及具有易感性/风险的遗传生物标志物疾病。中心假设是对STI产生的保护性和免疫病理反应与特征转录特征和遗传方差相关。这个项目的理由是确定对升高感染易感性和随后免疫病理风险的生物标志物加速理性疫苗设计和测试（i）确定最有可能从中受益的人免疫，以促进适当动力的研究，（ii）为疫苗试验提供平衡的群体选择，（iii）作为疫苗功效的临床指标。妇女的血传体转录分析衣原体生殖道感染的光谱揭示了与疾病相关的特定炎症途径并启用了诊断无症状感染妇女子宫内膜炎的生物标志物面板的定义带有高层负担。在强大的初步数据的指导下，以下三个特定目标将测试假设：1）确定候选生物标志物与上升的衣原体呈正相关或负相关无症状妇女感染； 2）确定具有上升衣原体易感性的遗传生物标志物感染和随后的生殖后遗症的风险； 3）确定引起疾病的途径及其关键使用因果网络分析，在上升衣原体感染过程中参与的调节器。第一个目标将配置来自局部感染或上部涉及到新队列的妇女的宫颈炎症反应高度暴露的妇女（TRAC2，核心B）。病原体负荷，共感染，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评估。其余的目标将集中在通过TRAC2和以前由Propired Cohorts整合基因型，基因表达和疾病表型表达定量性状基因座（EQTL）映射和因果中介试验，以及疾病鉴定因果基因，使用图形模型。在我们看来，提出的研究是创新的，因为它将在高度的与疾病有关的临床人群。拟议的研究很重要，因为它有望翻译直接进行人类的抗神经疫苗评估，并且对诊断和新型治疗剂的评估。