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到导致慢性盆腔疼痛、不孕症、异位妊娠和早产的组织损伤进展的客观标志物。拟议研究的长期目标是开发方法，以防止暴露于性传播病原体引起盆腔炎（PID）的妇女的性传播感染和生殖道后遗症。核心假设是，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。该应用程序的目的是识别这些关键途径，并开发和验证基于这些生物标志物的预测性临床仪器，其基本原理是该工具可用于识别易感个体。为了确定候选生物标志物和风险因素，并将其整合到预测工具中，并验证我们的假设，我们将在本提案的R21阶段追求以下具体目标：(1)通过对症状性PID女性子宫内膜组织活检中分离的RNA进行微阵列分析，确定沙眼衣原体感染期间最强烈调节的局部炎症和纤维化途径。(2)通过分析与性传播感染发病率和严重程度相关的单核苷酸多态性（snp），确定沙眼衣原体感染易感性和输卵管病变进展的标志物。这一贡献意义重大，因为这种筛查工具的开发将通过识别那些有可能因无症状感染而产生后遗症的人，直接使被诊断为活动性性传播感染的个体受益。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转录物签名；(2)与易感染和输卵管病理的遗传性状相关的snp将推动转运蛋白进入R33翻译阶段。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，并评估一组候选蛋白质生物标志物预测炎症的能力

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.