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

基本信息

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
项目类别：
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

项目摘要

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）：至关重要的是，从生殖道感染到组织损伤的目标标志物的客观标志物，导致慢性骨膜疼痛，不育，异位妊娠和过早分娩的病态。拟议研究的长期目标是开发用于预防性传播感染和生殖遗传后遗症的方法，暴露于性传播的病原体，导致骨盆炎性疾病（PID）。中心假设是，在宿主炎症和修复（纤维化）途径中存在预测生殖道疾病或遗传标志的生物标志物。本应用的目的是识别这些关键途径，并基于这些生物标志物来开发和验证预测性临床仪器，并以此理由认为该工具可用于识别脆弱的个体。为了确定候选生物标志物和要集成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阶段追求以下特定目标：（1）确定在基于Bira隔离的伴侣中，通过对rna隔离的疾病分析，确定在chlammydia trachomatis感染过程中最严格地调节了在chlammydia tharachomatis感染过程中，该途径与Ensoptial syopes coptope syops进行了分析。（2）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（SNP），确定了对沙眼感染易感性的标记和对输卵管病理的敏感性。这一贡献很重要，因为这种筛查工具的开发将直接使诊断为活动性传播感染的个体受益于诊断出患有后遗症风险的人，甚至是由于无症状感染而引起的。拟议的研究具有创新性，因为它结合了两种免费的方法来鉴定与PID及其后遗症相关的生物标志物。临界里程碑的实现：（1）PID转录本特征，以及（2）与遗传性状相关的SNP，易于感染和管状病理学，将推动拟议研究的转化蛋白转移到转化的R33阶段。这将包括一项无偏的基因组范围关联研究（GWAS），以找到遗传变异，以进一步定义后遗症的风险和评估蛋白质候选生物标志物的评估，以预测炎症的能力和疾病在临床环境中。在总的几年中，所有数据都将集成以开发一个预测模型，该模型将使用两个地理位置定义的女性，具有STI和生殖道疾病的高风险。这一贡献很重要，因为这种筛查工具的开发将直接使诊断为活动性传播感染的个体受益于诊断出患有后遗症风险的人，甚至是由于无症状感染而引起的。它还在评估新型疫苗和干预措施以防止生殖性病的情况下有广泛的应用。公共卫生相关性：拟议的研究与公共卫生有关，因为发现了一种可预测女性生殖道损害的临床可用工具，暴露于性传播病原体的女性中，对于评估候选疫苗候选者或旨在防止因感染引起的病态的新型疗法而言至关重要。因此，拟议的研究与NIH使命的一部分有关，即提供多用途预防策略，以增加全球用途以改善性和生殖健康。