Pharmacogenomics of Preterm Birth Prevention and Treatment

早产预防和治疗的药物基因组学

• 批准号: 8027598
• 负责人: TRACY A. MANUCK
• 金额: $ 13.72万
• 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/8027598
• 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; 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. PUBLIC HEALTH RELEVANCE: This proposal will contribute to increased understanding of SPTB therapies by identifying the subset of women most likely to respond to 17OHPC and indomethacin, which will allow us to work towards individualizing treatment, maximizing benefit and limiting side effects. This has the potential to lead to key intervention trials among other groups of pregnant women. These advances may result in individualized preterm birth interventions, which in turn could lower the overall rate of both primary and recurrent SPTB and its corresponding neonatal morbidity and mortality.

描述(申请人提供)：在美国，超过八分之一的婴儿是早产儿。尽管17-羟孕酮己酸酯(17OHPC)和消炎痛等药物可以预防和遏制一些女性的肺结核，但接受这些药物治疗的女性中仍有50%会早产。对不同反应的原因知之甚少，但可能是遗传因素造成的。这一职业发展奖旨在支持一名有前途的医生转变为一名独立的临床医生兼科学家，致力于研究自发早产的药物基因组学(SPTB)。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金。这份提案概述了一项培训和研究计划，该计划将提供5年的受保护的指导时间，并将Manuck博士转变为一名独立和自给自足的临床医生兼科学家。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)发展遗传和药物基因组数据的获取、管理和分析的额外技能，(3)发展临床试验设计和实施的额外技能，(4)发展领导多学科研究团队的技能，以及(5)进一步了解围产期遗传学研究的伦理和法律影响。这些目标将通过与导师(Michael Varner博士、Robert Silver博士和Lynn Jorde博士)的定期会议、完成几个研究证书和课程、与全国NICHD基因组学和蛋白质组学网络早产研究(GPN)中的SPTB专家合作以及出席国家会议来实现。具体的研究目标/假设是：(1)预防复发SPTB的17OHPC反应的变异是由于人类孕激素受体内的遗传变异引起的；(2)17OHPC预防复发SPTB的反应变异与细胞色素P450(CYP)-3A的遗传变异有关；(3)17OHPC(预防SPTB)和消炎痛(SPTB治疗)的反应变异与炎症途径的遗传变异有关。这些假说将通过分析生物样本(DNA和阴道拭子)和临床结果数据来验证，这些样本来自1500多名患有SPTB的妇女和1000名来自预期收集的GPN的仅足月分娩的对照妇女。已经招募了患者，收集了数据，提取了DNA。因此，这项研究设计为以患者为导向的职业发展奖提供了一种可行、有效和成本效益高的方法，该奖项旨在研究SPTB预防和治疗的药物基因组学。这项建议是获得多学科培训和研究经验的独特机会，同时在大量队列中将基因多态与特征良好的妊娠结局联系起来，并将支持这位临床医生兼科学家成为SPTB药物基因组学国家专家的目标。 公共卫生相关性：这项提案将通过确定最有可能对17OHPC和吲哚美辛有反应的妇女亚群，帮助提高对SPTB疗法的理解，这将使我们能够努力实现个体化治疗，最大限度地增加益处和限制副作用。这有可能导致在其他孕妇群体中进行关键的干预试验。这些进展可能导致个体化的早产干预，这反过来又可以降低原发和复发SPTB的总发病率及其相应的新生儿发病率和死亡率。