Identifying Biomarkers and Genetic Risk Factors Predictive of Reproductive Sequel

描述（由申请人提供）：迫切需要从生殖道感染进展到导致慢性骨盆疼痛、不孕、异位妊娠和早产发病的组织损伤的客观标志物。拟议研究的长期目标是开发方法，以预防暴露于导致盆腔炎（PID）的性传播病原体的妇女的性传播感染和生殖道后遗症。中心假设是预测生殖道疾病发展的生物标志物或风险增加的遗传标志物存在于宿主炎症和修复（纤维化）途径中。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个体。为了确定候选生物标志物和风险因素，以整合到一个预测工具，并测试我们的假设，我们将追求以下具体目标，在R21阶段的建议：（1）确定局部炎症和纤维化途径最强烈的沙眼衣原体感染期间进行基于微阵列的分析，从子宫内膜组织活检的RNA从症状性PID妇女获得。(2)确定对C.通过分析与STI的发病率和严重程度相关的单核苷酸多态性（SNPs）来评估沙眼感染和进展为输卵管病变的可能性。这一贡献意义重大，因为开发这一筛查工具将直接惠及被诊断患有活动性性传播感染的个人，因为它可以识别那些即使是无症状感染也有可能产生后遗症的人。拟议的研究是创新的，因为它结合了两种互补的方法来识别与PID及其后遗症相关的生物标志物。关键里程碑的实现：（1）PID转录本签名，以及（2）与易感染和输卵管病理学的遗传性状相关的SNP将推动过渡到拟议研究的翻译R33阶段。这将包括一项无偏倚的全基因组关联研究（GWAS），以发现进一步确定后遗症风险的遗传变异，并评估一组蛋白质候选生物标志物预测炎症的能力 和疾病的临床应用。在最后几年，所有数据将被整合，以开发一个预测模型，该模型将使用两个地理上界定的性传播感染和生殖道疾病高风险妇女队列进行测试。这一贡献意义重大，因为开发这一筛查工具将直接惠及被诊断患有活动性性传播感染的个人，因为它可以识别那些即使是无症状感染也有可能产生后遗症的人。它还广泛应用于评价新疫苗和预防生殖疾病的干预措施。 公共卫生相关性：拟议的研究与公共卫生有关，因为发现一种临床可用的工具来预测暴露于性传播病原体的妇女中女性生殖道损伤的发展，对于评估旨在预防感染引起的发病率的候选疫苗或新疗法至关重要。因此，拟议的研究与NIH的使命有关，该使命涉及提供多用途预防战略，以增加全球使用，以改善性健康和生殖健康。

DESCRIPTION (provided by applicant): There is a critical need for objective markers of progression from genital tract infection to tissue damage resulting in morbidities of chronic pelvi 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 transitin 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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the discovery of a clinically usable tool to predict development of female reproductive tract damage among women exposed to sexually transmitted pathogens is essential to the evaluation of vaccine candidates or novel therapies designed to prevent morbidities caused by infection. Thus, the proposed research is relevant to the part of NIH's mission that pertains to providing multipurpose prevention strategies to increase global use for better sexual and reproductive health.