Pharmacogenomics of Preterm Birth Prevention and Treatment

早产预防和治疗的药物基因组学

• 批准号: 8965542
• 负责人: TRACY A. MANUCK
• 金额: $ 5.53万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965542
• 关键词: Pharmacogenomics; Preterm; Birth; Prevention; Treatment

DESCRIPTION (provided by applicant): More than 1 in 8 babies in the US are born preterm. Although medications such as 17-alpha hydroxyprogesterone caproate (17OHPC) and indomethacin can prevent and arrest SPTB in some women, >50% of women who receive these medications will still deliver preterm. Reasons for variable responsiveness are poorly understood, but may be due to genetic factors. This career development award is designed to support the transition of a promising, physician into an independent clinician-scientist dedicated to the study of the pharmacogenomics of spontaneous preterm birth (SPTB). Dr. Manuck has the enthusiastic support of her Division, Department, and Institution, including at least 75% protected time and appropriate institutional funding. This proposal outlines a training and research program that will provide 5 years of protected mentored time and transition Dr. Manuck into an independent and self-sustaining clinician-scientist. The specific career development aims are to: (1) expand existing skills in study design, analysis, and interpretation of results, (2) develop additional skills in the acquisition, management, and analysis of genetic and pharmacogenomic data, (3) develop additional skills in the design and implementation of clinical trials, (4) develop skills for leadership of a multi-disciplinary research team, and (5) further understanding of ethical and legal implications of perinatal genetics research. These goals will be achieved through a combination of regular meetings with mentors (Drs. Michael Varner, Robert Silver, and Lynn Jorde), completion of several research certificates and courses, collaboration with SPTB experts nationwide in the NICHD Genomics and Proteomics Network for Preterm Birth Research (GPN), and attendance at national meetings. The specific research aims/hypotheses are: (1) Variation in response to 17OHPC for the prevention of recurrent SPTB results from genetic variation within the Human Progesterone Receptor (2) Variation in response to 17OHPC for the prevention of recurrent SPTB is associated with genetic variation in Cytochrome P450 (CYP) - 3A, and (3) Variation in response to 17OHPC (SPTB prevention) and indomethacin (SPTB treatment) is associated with genetic variation in inflammatory pathways. These hypotheses will be tested by analyzing biologic samples (DNA and vaginal swabs) and clinical outcome data on over 1500 women witeh1 SPTB and 1000 controls with only term deliveries from the prospectively collected GPN. Patients have been recruited, data have been collected, and DNA extracted. Thus, this study design represents a feasible, efficient, and cost-effective method for a patient-oriented career development award investigating the pharmacogenomics of SPTB prevention and treatment. This proposal represents a unique opportunity to gain multi-disciplinary training and research experience while correlating genetic polymorphisms with well-characterized pregnancy outcomes in a large cohort, and will support this Clinician-Scientist's goal of becoming a national expert in the pharmacogenomics of SPTB.

描述（由申请人提供）：在美国，超过八分之一的婴儿是早产儿。尽管17- α -羟孕酮己酸（17OHPC）和吲哚美辛等药物可以预防和遏制一些妇女的SPTB，但仍有50%的妇女接受这些药物治疗后会早产。不同反应的原因尚不清楚，但可能是由于遗传因素。该职业发展奖旨在支持有前途的医生转变为致力于自发性早产（SPTB）药物基因组学研究的独立临床医生科学家。Manuck博士得到了她所在部门、部门和机构的热情支持，包括至少75%的保护时间和适当的机构资助。该提案概述了一个培训和研究计划，该计划将提供5年的受保护指导时间，并将Manuck博士转变为一个独立的、自我维持的临床医生和科学家。具体的职业发展目标是：(1)扩展现有的研究设计、分析和结果解释方面的技能，(2)在遗传和药物基因组数据的获取、管理和分析方面培养额外的技能，(3)在临床试验的设计和实施方面培养额外的技能，(4)培养领导多学科研究团队的技能，(5)进一步理解围产期遗传学研究的伦理和法律含义。这些目标将通过与导师（博士）的定期会议相结合来实现。Michael Varner， Robert Silver和Lynn Jorde)，完成了几项研究证书和课程，与全国的新生儿和新生儿疾病研究基因组学和蛋白质组学网络（GPN）的SPTB专家合作，并参加了全国会议。具体的研究目的/假设是：(1)17OHPC预防SPTB复发的应答变异源于人孕激素受体的遗传变异；(2)17OHPC预防SPTB复发的应答变异与细胞色素P450 (CYP) - 3A的遗传变异有关；(3)17OHPC （SPTB预防）和吲哚美辛酸（SPTB治疗）的应答变异与炎症通路的遗传变异有关。这些假设将通过分析1500多名患有SPTB的妇女和1000名对照者的生物样本（DNA和阴道拭子）和临床结果数据进行检验，这些妇女仅从前瞻性收集的GPN中足月分娩。已经招募了患者，收集了数据，提取了DNA。因此，本研究设计为研究SPTB预防和治疗的药物基因组学的以患者为导向的职业发展奖项提供了一种可行、高效和具有成本效益的方法。这一建议为获得多学科培训和研究经验提供了一个独特的机会，同时将遗传多态性与大队列中具有良好特征的妊娠结局相关联，并将支持这位临床科学家成为SPTB药物基因组学国家专家的目标。