The role of HIF regulated genes and genomic regions in trophoblast invasion

描述（由申请方提供）：在胎盘发育早期，滋养层细胞排列在着床部位并侵入母体蜕膜，从而在母体和胎儿之间建立足够的血流。浅滋养层浸润与先兆子痫有关，先兆子痫是一种复杂的妊娠疾病，可能对母亲和孩子造成破坏性后果，并可能导致宫内生长受限（IUGR）。尽管滋养层细胞入侵的重要性，很少有人知道的基因组区域负责调控it. The拟议的项目将允许候选人结合联合收割机基因组学，计算生物学，和分子生物学研究滋养层细胞入侵的调控机制。在该项目的指导阶段，候选人将发现新的基因，基因组区域和调节滋养层侵袭的途径。具体而言，她将：（1）开发有助于研究胎盘发育和疾病的资源和计算工具;（2）鉴定滋养层侵入过程中活跃的基因和基因组区域。完成指导阶段将确保培训：建立一个具有计算基础设施的实验室;计算分析方面的进一步技术技能;研究胎盘发育和进行基因组编辑的其他分子生物学技术;以及与成为成功的独立首席研究员相关的职业发展技能。候选人的培训环境是开展拟议研究的理想环境。她的导师，指导委员会和斯坦福大学共同提供了一个优秀的培训计划，各种研究小组之间的广泛互动，以及一个良好的支持研究环境。她建立的资源，她开发的工具，她生成的数据，以及她在指导阶段获得的技能将是她独立研究的基础。在该项目的独立阶段，候选人将专注于她的滋养层细胞入侵研究的HIF途径，并将证明HIF调节区域的功能重要性。具体而言，她将：（1）鉴定滋养层侵袭期间HIF调节的基因和基因组区域;（2）验证HIF在侵袭性小鼠和人胎盘细胞中调节增强子的重要性;和（3）测量增强子对滋养层迁移和侵袭的贡献。这些研究将促进我们对滋养层细胞侵袭机制的有限理解，并可能为先兆子痫和IUGR的病因学提供见解。K99/R 00奖将帮助候选人实现她的最终目标，即建立一个基于计算和实验方法相结合的研究计划，以研究滋养层入侵背后的机制。

DESCRIPTION (provided by applicant): In early placental development, trophoblastic cells line the implantation site and invade the maternal decidua, thus establishing adequate blood flow between mother and fetus. Shallow trophoblast invasion has been associated with preeclampsia, a complex disease of pregnancy that can have devastating consequences on mother and child, and can result in Intrauterine Growth Restriction (IUGR). Despite the importance of trophoblast invasion, little is known about the genomic regions responsible for regulating it. The proposed project will allow the candidate to combine genomics, computational biology, and molecular biology to study the regulatory mechanisms underlying trophoblast invasion. During the mentored phase of this project, the candidate will uncover novel genes, genomic regions, and pathways regulating trophoblast invasion. Specifically, she will: (1) develop resources and computational tools that will aid in studying placental development and disease; and (2) identify genes and genomic regions active during trophoblast invasion. Completion of the mentored phase will ensure training in: setting up a lab with a computational infrastructure; further technical skills in computational analysis; additional molecular biology techniques to study placental development and perform genome editing; and career development skills relevant to being a successful independent principal investigator. The candidate's training environment is ideal for carrying out the proposed studies. Her mentor, mentoring committee, and Stanford University collectively provide an excellent training program, extensive interactions among a variety of research groups, and a well-supported research environment. The resources she builds, the tools she develops, the data she generates, and the skills she acquires during the mentored phase will be the foundation of her independent research. During the independent phase of this project, the candidate will focus her trophoblast invasion research on the HIF pathway, and will demonstrate the functional importance of HIF regulated regions. Specifically, she will: (1) identify HIF regulated genes and genomic regions during trophoblast invasion; (2) validate the importance of HIFs in regulating enhancers in invasive mouse and human placental cells; and (3) measure enhancer contribution to trophoblast migration and invasion. The proposed studies will advance our limited understanding of the mechanisms of trophoblast invasion and may provide insights into the etiology of preeclampsia and IUGR. The K99/R00 award will help the candidate achieve her ultimate goal of establishing a research program based on combined computational and experimental approaches to studying the mechanisms behind trophoblast invasion.