Pharmacogenetics of antenatal corticosteroids to improve neonatal outcomes

描述(申请人提供)：早产呈上升趋势，并导致严重的新生儿死亡率和发病率。不断扩大的药物遗传学领域有望提高医生照顾这些患者的能力。在这项建议中，大卫·M·哈斯博士建议在以患者为导向的临床研究中进行为期五年的全面指导培训，旨在通过药物遗传学改善早产引起的新生儿结局。候选人：哈斯博士是一名普通妇产科医生，具有基本的研究技能，并已在该研究领域发表了两篇背景文章。他的长期目标是成为产科和妇科的独立研究员，专注于早产和通过药物遗传学改善产科结果的研究。在这一临床领域需要新的、合格的研究人员。环境：在国际公认的研究员David Flockhart博士的指导下，以及一个优秀的联合导师和顾问小组的指导下，Haas博士将从事有重点的临床研究，并将在临床研究的所有方面接受正式和实用的指导。印第安纳大学医学院(IUSM)丰富的学术环境致力于哈斯博士作为一名独立内科科学家的发展，并拥有指导年轻研究人员的强大历史。作为他的K23计划的一部分，哈斯博士将完成IUSM临床研究人员培训强化计划，这将导致临床研究理学硕士学位。这将伴随着药物遗传学和实验室培训、发展研讨会和研究伦理培训。研究：这项应用的目的是评估药物遗传变异，这些变异可能导致早产时对产前皮质类固醇的反应改变新生儿结局。中心假设是糖皮质激素受体和代谢途径的药物遗传学差异与结局差异相关，并可能有助于确定最佳产前皮质类固醇给药方案。这项分两个阶段进行的研究计划检验了这一假设，并将1)检验细胞色素P450和磺基转移酶基因序列变异与新生儿结局之间的关联，2)检验糖皮质激素途径中的基因序列变异与产前糖皮质激素的药效反应变化之间的关联。这项研究的重要意义在于，改进了对早产和新生儿呼吸功能中糖皮质激素代谢和功能的药物遗传学理解，可能有助于改善结局和更好的治疗方案。这些研究将为未来的研究奠定基础，这些研究旨在将药物基因组学发现转化为改善早产妇女的治疗方案。与公共卫生的相关性：早产的后果严重影响家庭和社会。改善早产对新生儿的影响可以减少这种影响。这一K23奖项的最终目标是让哈斯博士成为一名独立的临床研究人员，专注于改善早产和其他疾病对母婴健康的影响。

DESCRIPTION (provided by applicant): Preterm birth is on the rise and leads to significant neonatal mortality and morbidity. The expanding field of pharmacogenetics promises to improve physicians' ability to care for these patients. In this proposal, Dr. David M. Haas proposes a comprehensive five-year period of mentored training in patient-oriented clinical research aimed at improving neonatal outcomes stemming from preterm birth through pharmacogenetics. Candidate: Dr. Haas is a general OB/GYN physician who possesses basic research skills and has already published two background articles in this research area. His long-term objective is to become an independent investigator in obstetrics and gynecology with a research focus on preterm labor and improving obstetric outcomes through pharmacogenetics. There is a need for new, wellqualified researchers in this clinical field. Environment: Under the mentorship of Dr. David Flockhart, an internationally recognized investigator, and a panel of excellent co-mentors and advisors, Dr. Haas will pursue focused clinical research and will receive formal and practical instruction in all aspects of clinical investigation. The rich academic environment of the Indiana University School of Medicine (IUSM) is committed to Dr. Haas's development as an independent physician scientist and has a strong history of mentoring young investigators. As part of his K23 plan, Dr. Haas will complete the IUSM Clinical Investigator Training Enhancement program which will lead to a Masters of Science in Clinical Research degree. This will be accompanied by pharmacogenetics and laboratory training, developmental seminars, and training in research ethics. Research: The objective of this application is to evaluate pharmacogenetic variations that may lead to altered neonatal outcomes in response to antenatal corticosteroids in preterm labor. The central hypothesis is that pharmacogenetic differences in the glucocorticoid receptors and metabolic pathway correlate with outcome disparities and may help determine optimal antenatal corticosteroid dosing regimens. The two-phased research plan tests that hypothesis and will 1) Test for associations between gene sequence variations in the cytochrome P450 and sulfotransferase enzymes and neonatal outcomes, and 2) Test for associations between gene sequence variations in the glucocorticoid pathway and variation in pharmacodynamic response to antenatal corticosteroids. The research is significant in that improved pharmacogenetic understanding of glucocorticoid metabolism and function in preterm labor and neonatal respiratory function may help lead to improved outcomes and better treatment regimens. These studies will lay the foundation for future research designed to translate pharmacogenomic findings into improved treatment regimens for women with preterm labor. Relevance to public health: Consequences of preterm birth significantly impact families and society. Improving neonatal outcomes from preterm birth can reduce this impact. The ultimate goal of this K23 award is for Dr. Haas to become an independent clinical researcher focused on improvements in maternal and infant health outcomes from preterm labor and other conditions.