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

促肾上腺皮质激素释放激素对胎盘转录网络和出生时间的作用

• 批准号: 10455047
• 负责人: Alison Genevieve Paquette
• 金额: $ 23.31万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455047
• 关键词: Adrenal Glands; Affect; Biological; Birth; Blood; CRISPR/Cas technology; Cell Line; Cells; Childhood; Computer software; Corticotropin; Corticotropin-Releasing Hormone; Data; Deoxyribonucleases; Early identification; Early treatment; Endocrine; Epidemiology; Fetal Development; Fetal Growth; Future; Gene Expression; Genes; Genetic Transcription; Gestational Age; Glucocorticoids; Goals; Grant; Growth; Growth and Development function; Health; Hormones; Human; Hypersensitivity; In Vitro; Knock-out; Knowledge; Learning; Length; Linear Regressions; Link; Maps; Measurement; Measures; Mediating; Mentors; Metabolic Pathway; Metabolism; Modeling; Molecular; Outcome; Overlapping Genes; Pathway Analysis; Pathway interactions; Placenta; Placental Biology; Plasma; Pregnancy; Premature Birth; Premature Labor; Price; Production; Regulation; Regulator Genes; Research; Research Personnel; Role; Sampling; Signal Transduction; Systems Biology; Techniques; Therapeutic Intervention; Tissues; Transcriptional Regulation; United States National Institutes of Health; Universities; Validation; Washington; Work; career; clinical biomarkers; cohort; differential expression; fetal; gene network; genome-wide; glucose transport; insight; interest; maternal stress; multidisciplinary; peptide hormone; post-doctoral training; prenatal environmental exposure; response; skills; software development; targeted treatment; transcription factor; transcription regulatory network; transcriptome; transcriptomics

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.

项目摘要 我的长期职业目标是使用数据驱动，建立独立的研究线 检查分娩的综合方法，我的兴趣位于糖皮质激素信号中 在怀孕。皮质营养素释放激素（CRH）是参与的肽激素 胎盘也产生的糖皮质激素信号传导。 CRH会影响胎盘生长 和功能，调节母体代谢，对于胎儿发育至关重要。胎盘CRH 在妊娠过程中释放到母体血浆中，在分娩前达到峰值，并且 妊娠中期的CRH升高可预测早产。中心假设 提议是，怀孕中期的CRH水平改变了胎盘基因表达景观，并且 下游对胎盘功能和妊娠长度的后果。这个多学科 项目将汇集各自领域的关键专家的院长；内森博士 Price（系统生物学），Sheela Sathyanarayana博士（流行病学）和Louis Muglia博士 （怀孕的内分泌调节）。通过在价格实验室内开发的软件，我们有 产生了人胎盘的大规模转录调节网络（TRN）。在这个 提出的分析，我们将扩展此trn，以确定与 使用来自大学的样品，母体血浆CRH和妊娠长度 华盛顿回声道路。在AIM 1中，我们将产生一个基因组宽的胎盘特异性 模拟转录因子及其靶基因之间的量化关系，并验证 该模型使用CRISPR/CAS9技术编辑关键转录因子并量化更改 在下游基因表达中。在AIM 2中，我们将确定与中期测得的CRH相关的基因 妊娠晚期以及与胎龄有关的基因，然后识别重叠的基因和 与这些基因相关的富集生物途径。在AIM 3中，我们将利用TRN确定 TF模块（基因的网络，其表达通过共同变化的基因网络 转录因子）与AIM 2中鉴定的差异表达基因相关的转录因子） 我们将通过胎盘衍生的细胞系在体外验证。这样，我们将确定 与母体等离子体CRH和妊娠长度有关的共享转录模块。我们 预计这项数据驱动的研究将发现涉及CRH在 分区和妊娠长度，并提供潜在的靶标，以延长妊娠长度 怀孕因早产而复杂。此外，这项工作将为我提供 建立独立的研究线所需的背景。

项目成果

The Placental Epigenome as a Molecular Link Between Prenatal Exposures and Fetal Health Outcomes Through the DOHaD Hypothesis.

• DOI: 10.1007/s40572-022-00354-8
• 发表时间: 2022-09
• 期刊: CURRENT ENVIRONMENTAL HEALTH REPORTS
• 影响因子: 7.9
• 作者: Lapehn, Samantha;Paquette, Alison G.
• 通讯作者: Paquette, Alison G.

SLC20a1/PiT-1 is required for chorioallantoic placental morphogenesis.

SLC20a1/PiT-1 是绒毛膜尿囊胎盘形态发生所必需的。

• DOI: 10.1530/vb-22-0018
• 发表时间: 2023
• 期刊: Vascular biology (Bristol, England)
• 作者: Correia-Branco,Ana;Mei,Ariel;Pillai,Sreehari;Jayaraman,Nirmala;Sharma,Radhika;Paquette,AlisonG;Neradugomma,NaveenK;Benson,Ciara;Chavkin,NicholasW;Mao,Qingcheng;Wallingford,MaryC
• 通讯作者: Wallingford,MaryC