Identifying Biomarkers and Genetic Risk Factors Predictive of Reproductive Sequel

识别预测生殖后果的生物标志物和遗传风险因素

• 批准号: 8265057
• 负责人: Toni Darville
• 金额: $ 16.72万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265057
• 关键词: Achievement; Acute; Animal Model; Biological Markers; Biopsy; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Chronic; Clinical; Clinical Data; Data; Detection; Development; Diagnosis; Disease; Disease Marker; Early Diagnosis; Early treatment; Ectopic Pregnancy; Endometrial; Epidemiologic Studies; Evaluation; Exposure to; Female; Fibrosis; Genetic; Genetic Markers; Genetic Risk; Genetic Variation; Genital system; Genome; Goals; High Risk Woman; Immune response; Incidence; Individual; Infection; Infertility; Inflammation; Inflammatory; Inflammatory Response; Intervention; Link; Measures; Mediating; Methods; Microarray Analysis; Mission; Morbidity - disease rate; Outcome; Pain; Pathology; Pathway interactions; Patients; Pelvic Inflammatory Disease; Phase; Play; Population Study; Predisposition; Premature Birth; Prevention strategy; Proteins; Public Health; RNA; Reproductive Health; Research; Risk; Risk Factors; Role; Screening procedure; Severities; Sexual Health; Sexually Transmitted Diseases; Single Nucleotide Polymorphism; Testing; Tissues; Transcript; Vulnerable Populations; Woman; base; chronic pelvic pain; cohort; cost; disease diagnosis; genetic risk factor; genome wide association study; innovation; instrument; novel; novel therapeutic intervention; novel vaccines; pathogen; predictive modeling; prevent; progression marker; repaired; reproductive; reproductive development; response; targeted delivery; therapeutic target; therapy design; tool; trait; vaccine candidate; vaccine efficacy

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.

描述（由申请人提供）：迫切需要从生殖道感染到导致慢性骨盆疼痛、不孕症、宫外孕和早产等疾病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来预防暴露于导致盆腔炎（PID）的性传播病原体的女性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临床工具，其基本原理是该工具可用于识别易受影响的个体。为了确定可整合到预测工具中的候选生物标志物和风险因素并检验我们的假设，我们将在该提案的 R21 阶段追求以下具体目标：（1）通过对从有症状 PID 的女性子宫内膜组织活检中分离出的 RNA 进行基于微阵列的分析，确定沙眼衣原体感染过程中受最强烈调节的局部炎症和纤维化途径。 (2) 通过分析与 STI 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理进展的标志物。这一贡献意义重大，因为该筛查工具的开发将通过识别那些因无症状感染而有后遗症风险的人，直接使被诊断患有活动性性传播感染的个人受益。拟议的研究具有创新性，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 转录本特征，以及 (2) 与易感染和输卵管病理的遗传特征相关的 SNP，将推动转运蛋白进入拟议研究的转化 R33 阶段。这将包括一项公正的全基因组关联研究（GWAS），以寻找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 和临床环境中的疾病。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定义的性传播感染和生殖道疾病高风险女性群体进行测试。这一贡献意义重大，因为该筛查工具的开发将通过识别那些因无症状感染而有后遗症风险的人，直接使被诊断患有活动性性传播感染的个人受益。它还广泛应用于评估新型疫苗和预防生殖疾病的干预措施。 公共健康相关性：拟议的研究与公共健康相关，因为发现一种临床上可用的工具来预测暴露于性传播病原体的女性生殖道损伤的发展对于评估候选疫苗或旨在预防感染引起的发病的新疗法至关重要。因此，拟议的研究与 NIH 使命的一部分相关，即提供多用途预防策略，以增加全球使用，以改善性健康和生殖健康。