Identifying Biomarkers and Genetic Risk Factors Predictive of Reproductive Sequel

迫切需要从生殖道感染到组织损伤进展的客观标志物 导致慢性骨盆疼痛、不孕、异位妊娠和早产的发病率。长 拟议研究的长期目标是开发预防性传播感染的方法， 暴露于性传播病原体的女性生殖道后遗症， 炎症性疾病（PID）。中心假设是预测生殖发育的生物标志物， 在宿主炎症和修复（纤维化）中存在增加风险的道疾病或遗传标记 途径。本申请的目的是确定这些关键途径，并开发和验证 基于这些生物标志物的预测性临床工具，其基本原理是该工具可用于识别 脆弱的个体。确定候选生物标志物和风险因素，以整合到预测工具中 为了检验我们的假设，我们将在本提案的R21阶段追求以下具体目标：（1） 确定沙眼衣原体感染过程中最强烈调节的局部炎症和纤维化途径 通过对从子宫内膜组织活检中分离的RNA进行基于微阵列的分析， 从有症状的PID女性身上。(2)确定对C.沙眼感染和 通过分析与发病率相关的单核苷酸多态性（SNP）， 性传播感染的严重程度。这一贡献意义重大，因为开发这一筛选工具将直接受益于 通过识别那些即使无症状性传播感染也有后遗症风险的人， 感染拟议的研究是创新的，因为它结合了两种互补的方法， 鉴定与PID及其后遗症相关的生物标志物。实现关键里程碑：（1）PID 转录本签名，和（2）与易感染和输卵管炎的遗传性状相关的SNP 病理学将推动过渡到拟议研究的转化R33阶段。这将包括 无偏见的全基因组关联研究（GWAS），以发现进一步确定风险的遗传变异， 后遗症和评估一组蛋白候选生物标志物预测炎症和 在临床环境中的疾病。在最后几年，所有的数据将被整合，以制定一个预测 该模型将使用两个地理上界定的性传播感染高危妇女群体进行测试， 生殖道疾病这一贡献意义重大，因为开发这一筛选工具将 直接受益于诊断为活动性STI的个人， 无症状感染者。它还广泛应用于评价新型疫苗和干预措施， 预防生殖疾病。

There is a critical need for objective markers of progression from genital tract infection to tissue damage resulting in morbidities of chronic pelvic pain, infertility, ectopic pregnancy and premature delivery. The long term goal of the proposed research is to develop methods to prevent sexually transmitted infection and reproductive tract sequelae in women exposed to sexually transmitted pathogens that cause pelvic inflammatory disease (PID). The central hypothesis is that biomarkers that predict development of reproductive tract disease or genetic markers of increased risk are present in host inflammatory and repair (fibrogenic) pathways. The objective of this application is to identify these key pathways and develop and validate a predictive clinical instrument based on these biomarkers, with the rationale that this tool can be used to identify vulnerable individuals. To identify candidate biomarkers and risk factors to be integrated into a predictive tool and to test our hypothesis we will pursue the following specific aims during the R21 phase of this proposal: (1) Identify the local inflammatory and fibrotic pathways most strongly regulated during Chlamydia trachomatis infection by performing microarray-based analysis of RNA isolated from endometrial tissue biopsies obtained from women with symptomatic PID. (2) Identify markers for susceptibility to C. trachomatis infection and for progression to tubal pathology by analysis of single nucleotide polymorphisms (SNPs) linked to incidence and severity of STI. This contribution is significant because development of this screening tool will directly benefit individuals diagnosed with active STI by identifying those at risk for sequelae arising from even asymptomatic infection. The proposed research is innovative because it combines two complimentary approaches for the identification of biomarkers associated with PID and its sequelae. Achievement of critical milestones: (1) a PID transcript signature, and (2) SNPs associated with genetic traits that predispose to infection and tubal pathology will drive transition to the translational R33 phase of the proposed research. This will include an unbiased Genome Wide Association Study (GWAS) to find genetic variations that further define risk for sequelae and evaluation of a panel of protein candidate biomarkers for their ability to predict inflammation and disease in a clinical setting. In the concluding years, all of the data will be integrated to develop a predictive model that will be tested using two geographically defined cohorts of women at high risk for STI and reproductive tract disease. This contribution is significant because development of this screening tool will directly benefit individuals diagnosed with active STI by identifying those at risk for sequelae arising from even asymptomatic infection. It also has broad application to evaluation of novel vaccines and interventions to prevent reproductive morbidities.