Identifying Biomarkers and Genetic Risk Factors Predictive of Reproductive Sequel

描述(申请人提供)：从生殖道感染到导致慢性盆腔疼痛、不孕不育、宫外孕和早产等疾病的组织损伤，迫切需要客观的进展标记。这项拟议研究的长期目标是开发方法，预防暴露在性传播病原体中的女性受到性传播感染和生殖道后遗症，这些病原体会导致盆腔炎(PID)。中心假设是，预测生殖道疾病发展的生物标记物或风险增加的遗传标记物存在于宿主炎症和修复(纤维化)途径中。此应用程序的目标是识别这些关键途径，并开发和验证基于这些生物标记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。为了确定可以整合到预测工具中的候选生物标记物和风险因素，并检验我们的假设，我们将在这项提议的R21阶段追求以下特定目标：(1)通过对从有症状的痛经妇女的子宫内膜组织活检中提取的RNA进行基于微阵列的分析，确定在沙眼衣原体感染过程中调控最强烈的局部炎症和纤维化途径。(2)通过分析与沙眼衣原体感染的发病率和严重程度相关的单核苷酸多态性(SNPs)，确定沙眼衣原体感染的易感性和进展为输卵管病变的标志。这一贡献意义重大，因为这一筛查工具的开发将通过识别那些即使是无症状感染也有后遗症风险的人，直接使被诊断为活动期STI的个人受益。这项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盆腔炎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的遗传特征相关的SNPs将推动过渡到拟议研究的翻译R33阶段。这将包括一项无偏见的基因组广泛关联研究(GWAS)，以发现进一步确定后遗症风险的基因变异，并评估一组蛋白质候选生物标记物预测炎症的能力 以及临床环境中的疾病。在最后几年，将整合所有数据，以开发一个预测模型，该模型将使用两个地理上确定的性传播感染和生殖道疾病高危妇女队列进行测试。这一贡献是重要的，因为这一筛查工具的开发将通过识别那些即使是无症状感染也有后遗症风险的人，直接使被诊断为活动期STI的个人受益。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相关，因为发现一种临床上可用的工具来预测性传播病原体暴露的妇女中女性生殖道损害的发展，对于评估候选疫苗或旨在预防感染引起的疾病的新疗法至关重要。因此，拟议的研究与美国国立卫生研究院的使命有关，该使命涉及提供多用途预防战略，以增加全球对更好的性健康和生殖健康的使用。

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.