Pharmacogenomics of Preterm Birth Prevention and Treatment

早产预防和治疗的药物基因组学

• 批准号: 8429434
• 负责人: TRACY A. MANUCK
• 金额: $ 13.18万
• 依托单位: UNIVERSITY OF UTAH
• 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/8429434
• 关键词: 7q21; 7q22; Accounting; Acute; Address; Admixture; Adverse effects; African American; Anti-Inflammatory Agents; Anti-inflammatory; Area; Authorization documentation; Award; CYP3A4 gene; Camping; Candidate Disease Gene; Cervical; Chromosomes; Clinical; Clinical Trials; Collaborations; DNA; Data; Development Plans; Enzymes; Ethics; Fellowship; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genetic Variation; Genomics; Genotype; Goals; Haplotypes; High Risk Woman; Human; Hydroxyprogesterone Caproate; Indomethacin; Infant; Inflammation; Inflammatory; Institution; Intervention; Intervention Trial; K-Series Research Career Programs; Lead; Leadership; Logistic Regressions; Maps; Mentors; Metabolic; Metabolism; Methods; National Institute of Child Health and Human Development; Neonatal Mortality; Outcome; Pathway interactions; Patients; Perinatal; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Physicians; Placebos; Populations at Risk; Pregnancy Outcome; Pregnant Women; Premature Birth; Prevention; Process; Progesterone; Progesterone Receptors; Prolonged Pregnancy; Prophylactic treatment; Prostaglandins; Proteomics; Recruitment Activity; Recurrence; Research; Research Design; Research Training; Role; Sampling; Scientist; Silver; Single Nucleotide Polymorphism; Site; Swab; Testing; Therapeutic Intervention; Time; Tocolysis; Tocolytic Agents; Training; Universities; Utah; Vagina; Variant; Woman; Work; base; career; career development; cohort; cost effective; cytochrome P450 3A; cytokine; data acquisition; design; experience; fetal; gene environment interaction; genetic analysis; genetic epidemiology; legal implication; meetings; neonatal morbidity; patient oriented; premature; prevent; programs; public health relevance; response; skills; skills training; ward

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早产。虽然药物如17-α-羟孕酮己酸酯（17 OHPC）和吲哚美辛可以预防和阻止一些妇女的SPTB，但接受这些药物的妇女仍有50%以上会早产。可变反应性的原因知之甚少，但可能是由于遗传因素。这个职业发展奖旨在支持一个有前途的医生转变为一个独立的临床科学家，致力于自发性早产（SPTB）的药物基因组学研究。Manuck有她的司，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金。该提案概述了一项培训和研究计划，该计划将提供5年受保护的指导时间，并将Manuck博士转变为独立和自我维持的临床医生-科学家。 具体的职业发展目标是：（1）扩展研究设计，分析和结果解释的现有技能，（2）开发遗传和药物基因组学数据的获取，管理和分析的额外技能，（3）开发临床试验设计和实施的额外技能，（4）开发多学科研究团队的领导技能，（5）进一步认识围产期遗传学研究的伦理和法律的含义。这些目标将通过与导师（Michael Varner博士，Robert银和林恩乔德）定期会议，完成几项研究证书和课程，与全国范围内的SPTB专家在NICHD基因组学和蛋白质组学网络早产研究（GPN）中的合作以及参加国家会议来实现。 具体的研究目标/假设是：（1）响应于17 OHPC预防复发性SPTB的变异是由人预后素受体内的遗传变异引起的（2）响应于17 OHPC预防复发性SPTB的变异与细胞色素P450（CYP）-3A的遗传变异有关，（3）对17 OHPC（SPTB预防）和吲哚美辛（SPTB治疗）的应答变异与炎症途径的遗传变异相关。将通过分析来自前瞻性收集的GPN的1500多名SPTB妇女和1000名仅足月分娩的对照妇女的生物样本（DNA和阴道拭子）和临床结局数据来检验这些假设。已经招募了病人，收集了数据，提取了DNA。因此，这项研究设计代表了一种可行的，有效的，具有成本效益的方法，以患者为导向的职业发展奖调查SPTB的预防和治疗的药物基因组学。 该提案代表了获得多学科培训和研究经验的独特机会，同时将遗传多态性与大型队列中的良好妊娠结局相关联，并将支持这位临床医生-科学家成为SPTB药物基因组学国家专家的目标。