The Role of Corticotrophin Releasing Hormone on Placental Transcriptional Networks and Birth Timing

项目总结 我的长期职业目标是利用数据驱动建立一条独立的研究路线， 检查分娩的综合方法，我的兴趣在于糖皮质激素信号 在怀孕期间。促肾上腺皮质激素释放激素(CRH)是一种多肽类激素，参与 糖皮质激素信号也是由胎盘产生的。促性腺激素释放激素影响胎盘生长 和功能，调节母体新陈代谢，对胎儿发育至关重要。胎盘CRH 在怀孕过程中释放到母体血浆中，在分娩前达到顶峰，并且 孕中期CRH升高预示早产。这一点的中心假设是 有观点认为，妊娠中期的CRH水平改变了胎盘基因的表达格局， 对胎盘功能和妊娠长度的下游影响。这是一个多学科的 项目将汇集合作导师，他们都是各自领域的关键专家； 普莱斯(系统生物学)、Sheela Sathyanarayana博士(流行病学)和Louis Muglia博士 (妊娠的内分泌调节)。通过在价格实验室中开发的软件，我们拥有 产生了人类胎盘的大规模转录调控网络(TRN)。在这 建议的分析，我们将扩展此TRN以确定与以下相关的共享转录驱动因素 母体血浆促肾上腺皮质激素释放激素和孕期长度，使用来自加州大学的样本 华盛顿的回声路径。在目标1中，我们将生成全基因组、特定于胎盘的 建立转录因子与其目标基因之间的量化关系模型，并验证 该模型使用CRISPR/Cas9技术编辑关键转录因子并量化变化 下游基因的表达。在目标2中，我们将识别与MID中测量的CRH相关的基因 以及与孕龄相关的基因，然后识别重叠的基因和 丰富了与这些基因相关的生物途径。在目标3中，我们将利用TRN来确定 转录因子模块(基因网络，其表达通过共同的 转录因子)与目标2中鉴定的差异表达基因相关， 我们将通过胎盘来源的细胞系在体外进行验证。通过这种方式，我们将识别 共享与母体血浆促肾上腺皮质激素释放激素和妊娠长度相关的转录模块。我们 预计这项数据驱动的研究将揭示CRH在 分割和妊娠长度，并提供潜在的目标，以延长妊娠长度 妊娠合并早产。此外，这项工作将为我提供 背景需要建立一条独立的研究路线。

PROJECT SUMMARY My long-term career objective is to establish an independent line of research using data driven, integrated approaches to examine parturition, and my interests lie within glucocorticoid signaling in pregnancy. Corticotrophin releasing hormone (CRH) is a peptide hormone involved in glucocorticoid signaling that is also produced by the placenta. CRH influences placental growth and function, modulates maternal metabolism, and is crucial for fetal development. Placental CRH is released into maternal plasma over the course of gestation, peaking before parturition, and elevated CRH in mid gestation is predictive of preterm birth. The central hypothesis of this proposal is that CRH levels in mid pregnancy alter the placental gene expression landscape, with downstream consequences on placental function and gestational length. This multidisciplinary project will bring together co-mentors who are key experts in their respective fields; Dr. Nathan Price (systems biology), Dr. Sheela Sathyanarayana (epidemiology) and Dr. Louis Muglia (endocrine regulation of pregnancy). Through software developed within in the Price lab, we have generated a large scale transcriptional regulatory network (TRN) of the human placenta. In this proposed analysis, we will expand this TRN to identify shared transcriptional drivers related to both maternal plasma CRH and gestational length, using samples from the University of Washington ECHO PATHWAYS. In aim 1, we will generate a genome wide, placental specific model quantifying relationships between transcription factors and their target genes, and validate this model using CRISPR/Cas9 technology to edit key transcription factors and quantify changes in downstream gene expression. In aim 2, we will identify genes related to CRH measured in mid to late gestation as well as genes related to gestational age, then identify overlapping genes and enriched biological pathways related to these genes. In aim 3, we will leverage the TRN to identify TF modules (networks of genes whose expression coordinately changes through a common transcription factor) which are related to the differentially expressed genes identified in aim 2, which we will validate in vitro through placental derived cell lines. In this way, we will identify shared transcriptional modules related to maternal plasma CRH and gestational length. We anticipate that this data driven study will uncover molecular mechanisms involving CRH's role in partition and gestational length, and provide potential targets to lengthen gestational length in pregnancies complicated by preterm birth. Additionally, this work will provide me with the background needed to establish an independent line of research.