Integrative Longitudinal Genomics of Maternal Asthma-Preeclampsia Overlap and Risk of Childhood Asthma

摘要- 该项目的目标是在基因组分析中使用系统的综合计算方法 寻找与先兆子痫 (PE) 和产前重叠的新基因、生物网络和途径 母亲哮喘是 PE 和儿童哮喘的危险因素。在这种方法中，我们将整合两个 来自下一代测序 (mRNA-miRNA seq) 的基因组学数据类型，以发现新的 导致儿童哮喘风险的生物学途径。具体目标依赖于纵向高吞吐量 妊娠 10-18 周和 32-38 周时对患有哮喘和哮喘的母亲进行外周血 RNA 测序 维生素 D 产前哮喘减少试验 (VDAART) 中的 PE 和脐带血。我们会 在第二组妊娠 (LifeCodes) 中复制疾病模块和生物学候选物。 该项目目标的成功实现将有助于识别早期诊断的生物标志物 PE 以及导致妊娠期间和未来 PE 和母亲哮喘的基因组因素 计划将这些发现转化为预防肺栓塞和儿童哮喘的临床实践。 该项目将由医学博士、博士、理学硕士 Hooman Mirzakhani 领导，他是 布莱根妇女医院 (BWH) 网络医学科 (CDNM) 的钱宁分部。期间 在接受培训后，他获得了哈佛大学生物医学信息学医学硕士学位 莱顿医学院和药物遗传学和药物基因组学哲学博士 荷兰大学医学中心。在 CDNM，他一直致力于流行病学和 PE 早期起源、妊娠期哮喘、维生素 D 在哮喘中的作用的基因组研究 和 PE，特别关注哮喘和维生素 D 对 PE 发展的继发影响和 儿童哮喘的风险。 Mirzakhani 博士计划在转化学术领域发展自己的职业生涯 生物医学科学。该提案的成功完成将带来系统生物学的高级培训 未来作为科学家的独立职业需要阐明儿童哮喘的早期起源和 其产前危险因素，包括导致母婴发病的妊娠期高血压疾病 并影响母亲和新生儿的长期健康。 Mirzakhani 博士将使用 VDAART 的样本 发现阶段的研究和用于复制的其他受试者样本将由 Dr. McElrath，BWH 母胎医学部 LifeCodes 队列的 PI。他将受到指导 并由 Scott T. Weiss（医学博士、理学硕士）和 Joseph Loscalzo（医学博士、哲学博士、文学硕士）、Thomas F. McElrath（医学博士）提供建议， 博士、Albert-Laszlo Barabasi 博士和 Vincent J. Carey 博士组成的多学科专家团队 临床、生物医学、生物统计和转化研究领域的领导者，拥有出色的记录 指导年轻研究人员走向独立研究生涯。

Abstract- The goal of this project is to use a systematic and integrative computational approach in genomic analysis to find novel genes, biological networks and pathways overlapping preeclampsia (PE) and prenatal maternal asthma as a risk factor for both PE and childhood asthma. In this approach, we will integrate two types of genomics data derived from Next-Generation Sequencing (mRNA-miRNA seq), to discover new biological pathways conferring risk of childhood asthma. Specific aims rely on longitudinal high throughput sequencing of maternal peripheral blood RNA at 10-18 and 32-38 weeks of pregnancies with asthma and PE and cord blood at delivery in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). We will replicate the disease module and biological candidates in a second cohort of pregnancies (LifeCodes). Successful achievement of the objective of this project will help to identify biomarkers for early diagnosis of PE, and genomic factors contributing to both PE and maternal asthma during pregnancy as well as a future plan for translation of these discoveries into clinical practice for prevention of PE and childhood asthma. The project will be led by Hooman Mirzakhani, MD, PhD, MMSc who is an Instructor in Medicine at Channing Division of Network Medicine Division (CDNM) at Brigham and Women’s Hospital (BWH). During his training, he has received a Master of Medical Science degree in Biomedical Informatics from Harvard Medical School and a Doctor of Philosophy in Pharmacogenetics and Pharmacogenomics from Leiden University Medical Center, The Netherlands. At the CDNM, he has been pursing epidemiologic and genomic investigations into the early origins of PE, asthma during pregnancy, role of vitamin D in asthma and PE with a particular interest in secondary influences of asthma and vitamin D on PE development and risk of childhood asthma. Dr. Mirzakhani plans to develop his career in the academic field of translational biomedical science. Successful completion of this proposal will result in advanced training in systems biology required for a future independent career as a scientist to elucidate the early origins of childhood asthma and its prenatal risk factors including hypertensive disorders of pregnancy that cause maternal-fetal morbidity and affect mother and neonates’ long-term health. Dr. Mirzakhani will use samples from the VDAART study for the discovery phase and additional subjects’ samples for replication will be provided by Dr. McElrath, PI of the LifeCodes cohort at Division of Maternal-Fetal Medicine at BWH. He will be mentored and advised by Scott T. Weiss, MD, MS, and Joseph Loscalzo, MD, PhD, MA, Thomas F. McElrath, MD, PhD, Albert-Laszlo Barabasi, PhD, and Vincent J. Carey, PhD, a multidisciplinary team of experts and leaders in clinical, biomedical, biostatistical and translational research with excellent track records of mentoring young investigators towards independent research careers.