Pharmacogenomics of Preterm Birth Prevention and Treatment

早产预防和治疗的药物基因组学

• 批准号: 8217186
• 负责人: TRACY A. MANUCK
• 金额: $ 13.32万
• 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/8217186
• 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. 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（由申请人提供）：在美国，超过八分之一的婴儿是早产。尽管诸如17-α-羟基丙酮（17OHPC）和吲哚美辛等药物可以预防和逮捕一些女性，但接受这些药物的妇女中，有50％的妇女仍将提供早产。响应能力的原因很少，但可能是由于遗传因素引起的。该职业发展奖旨在支持有前途的，医师向独立的临床医生转变，专门研究自发早产（SPTB）的药物基因组学。玛雅克博士得到了她的部门，部门和机构的热情支持，其中包括至少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年的受保护的指导时间，并将Manuck博士转变为独立和自我维持的临床医生。 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.这些目标将通过与导师（Michael Varner博士，Robert Silver和Lynn Jorde博士）结合结合，完成了几项研究证书和课程，与全国NICHD基因组学网络和蛋白质组学网络中的SPTB专家合作（GPN）（GPN）以及参加全国会议的SPTB专家的合作。 具体研究的目的/假设是：（1）响应于17OHPC预防复发性SPTB的变化，这是由于人孕激素受体内遗传变异（2）响应于17OHPC预防复发SPTB的变化（2）与Cytoterrent SPTB预防相关的变化与Cytotrome SPTB的预防与CytoCrome差异有关（CYP）p450（cyp） - 3A和（3A）的遗传变异（3A）和（3a）变化（3A）（3A）（3a）变化（3A）（3A）（3A）（3A）。吲哚美辛（SPTB治疗）与炎症途径的遗传变异有关。这些假设将通过分析生物学样本（DNA和阴道拭子）以及1500多名女性WITEH1 SPTB和1000个对照的临床结果数据来检验，并且仅从前瞻性收集的GPN进行了术语。已经招募了患者，收集了数据并提取了DNA。因此，这项研究设计代表了一种可行，高效且具有成本效益的方法，用于调查SPTB预防和治疗的药物基因组学，以患者为导向的职业发展奖。 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特征良好的妊娠结局相关联，并将支持该临床医生 - 科学家成为SPTB药物基因组学的国家专家的目标。 公共卫生相关性：该提案将通过确定最有可能对17OHPC和吲哚美辛做出反应的妇女子集的子集来增加对SPTB疗法的理解，这将使我们能够致力于个体化治疗，最大程度地提高利益和限制副作用。这有可能导致其他孕妇进行关键干预试验。这些进步可能会导致个性化早产，这又可以降低原发性和复发性SPTB的总体速率及其相应的新生儿发病率和死亡率。