Pharmacogenetics of antenatal corticosteroids to improve neonatal outcomes

描述（由申请人提供）：早产正在上升，并导致显着的新生儿死亡率和发病率。药物遗传学领域的不断扩大有望提高医生照顾这些患者的能力。在这项提案中，大卫M。哈斯提出了一个全面的五年期的指导培训，以病人为导向的临床研究，旨在改善新生儿的结果，从早产通过药物遗传学。候选人：哈斯博士是一位普通的妇产科医生，他拥有基本的研究技能，并在该研究领域发表了两篇背景文章。他的长期目标是成为妇产科的独立研究者，研究重点是早产和通过药物遗传学改善产科结局。这一临床领域需要新的、合格的研究人员。工作环境：在国际公认的研究者大卫弗洛克哈特博士和一组优秀的共同导师和顾问的指导下，哈斯博士将从事重点临床研究，并将在临床研究的各个方面接受正式和实用的指导。印第安纳州大学医学院（IUSM）丰富的学术环境致力于哈斯博士作为一名独立的医生科学家的发展，并具有指导年轻研究人员的悠久历史。作为他的K23计划的一部分，哈斯博士将完成IUSM临床研究者培训增强计划，这将导致在临床研究学位科学硕士。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。调研：本申请的目的是评价药物遗传学变异，可能导致早产儿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果差异相关，并可能有助于确定最佳的产前皮质类固醇给药方案。两阶段研究计划测试该假设，并将1）测试细胞色素P450和磺基转移酶的基因序列变异与新生儿结局之间的关联，2）测试糖皮质激素途径中的基因序列变异与产前皮质类固醇药效学反应变异之间的关联。这项研究的重要性在于，提高对糖皮质激素代谢和功能在早产和新生儿呼吸功能中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，旨在将药物基因组学研究结果转化为改善早产妇女的治疗方案。与公共卫生的相关性：早产的后果对家庭和社会产生重大影响。改善早产的新生儿结局可以减少这种影响。这个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的母婴健康结果。

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.