Identifying Biomarkers and Genetic Risk Factors Predictive of Reproductive Sequel

从生殖道感染到组织损伤，迫切需要客观的标记物 导致慢性盆腔疼痛、不孕不育、宫外孕和早产的发病率。《长河》 拟议研究的长期目标是发展防止性传播感染的方法和 暴露于引起盆腔的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 肠道疾病或风险增加的遗传标记存在于宿主炎症和修复(纤维性)中 小路。此应用程序的目标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，其原理是该工具可用于识别 脆弱的个体。确定要集成到预测工具中的候选生物标记物和风险因素 为了验证我们的假设，我们将在本提案的R21阶段实现以下具体目标：(1) 确定沙眼衣原体感染过程中调节最强的局部炎症和纤维化途径 通过对从子宫内膜组织活检中提取的RNA进行基于微阵列的RNA分析来实现感染 来自有症状性盆腔炎的女性。(2)确定沙眼衣原体感染的易感性标志物和 单核苷酸多态(SNPs)与输卵管病变发病相关的研究进展 性传播感染的严重性。这一贡献意义重大，因为这一筛查工具的开发将直接受益 通过识别有后遗症风险的人被诊断为活动期性传播感染，即使是无症状的 感染。这项拟议的研究具有创新性，因为它结合了两种互补的方法 前列腺癌及其后遗症相关生物标志物的鉴定。关键里程碑的实现：(1)PID 转录签名，以及(2)与易感染和输卵管的遗传特征相关的SNPs 病理学将推动过渡到拟议研究的翻译R33阶段。这将包括一个 无偏见的基因组广泛关联研究(GWAS)，以发现进一步定义风险的遗传变异 后遗症和一组蛋白质候选生物标记物预测炎症和 临床环境中的疾病。在最后几年，所有数据将被整合起来，以制定一个预测性的 该模型将使用两个地理上定义的STI和STI高危女性队列进行测试 生殖道疾病。这一贡献意义重大，因为这一筛查工具的开发将 直接受益于被诊断为活动期性传播感染的人，因为他们发现了因 无症状感染。它还广泛应用于新疫苗的评估和干预措施 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.