Uterine Vascular Remodeling during Pregnancy

妊娠期子宫血管重塑

基本信息

批准号：
8509238
负责人：
James K Pru
金额：
$ 21.54万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-13 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8509238
关键词：
Angiotensinogen Attention Automobile Driving Biocompatible Materials Blood Pressure Blood Vessels Cells Clinical Code Communication Conceptions Decidual Cell Reactions Development Embryo Endometrial Stromal Cell Endometrium Environment Enzymes Epithelial Epithelium Event Failure Family Family member Funding Mechanisms Future G-Protein-Coupled Receptors GTP-Binding Proteins Genes Genetic Health Human Implant In Situ Hybridization In Vitro Insertional Mutagenesis Intention Laboratories Light Link Mediating Mediator of activation protein Mesenchymal Molecular Morbidity - disease rate Mothers Mus Mutagenesis Mutant Strains Mice NIH Program Announcements Nitric Oxide Synthase Nutrient Organ Patient currently pregnant Pattern Peptides Physiology Placenta Play Polyploidy Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Maintenance Pregnancy Outcome Pregnancy loss Process Proliferating Prostaglandin Production Prostaglandins Receptor Gene Receptor Signaling Recurrence Renin Renin-Angiotensin System Reproductive Biology Research Research Project Grants Resources Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Spontaneous abortion Staging Stromal Cells Technology Testing Tissues Uterus Vascular remodeling Vasodilation Woman Work angiotensin I (1-7)animal model development embryo/fetus fetal hemodynamics human GPRC5C protein in vivo member mortality mouse model novel paracrine promoter public health relevance receptor receptor expression recombinase reproductive research study response synthetic enzyme tool transgene expression

项目摘要

DESCRIPTION (provided by applicant): Our laboratory recently identified a novel murine G-protein coupled receptor (GPCR) that becomes up- regulated (7-fold) in the decidualizing stromal compartment in response to the implanting embryo. RT-PCR and in situ hybridization reveal that the novel GPCR is temporally and spatially restricted in its expression pattern to the stromal compartment of the uterus during pregnancy and is not expressed in other tissues/organs. Studies using human decidualized stromal cells suggest that a functional counterpart is expressed during human decidualization. The proposed studies will therefore have likely implications for human pregnancy. Likewise, it was established that renin, an enzyme that generates active hemodynamic peptides through proteolytic cleavage of angiotensinogen, is up-regulated in the endometrium during early gestation. Our hypothesis is that the orphaned GPCR is functionally required for normal pregnancy, and that this novel receptor serves to mediate angiotensin-(1-7)-induced vasodilation at the maternal-embryo interface. In Specific Aim 1 we propose to demonstrate the functional requirement of the receptor in insertional mutagenesis studies in which cre recombinase is inserted into the receptor gene locus. Particular focus will be given to uterine vascular dynamics and prostaglandin production during early pregnancy. One important aspect of generating the GPCR-cre mouse line is that, due to the restricted expression of the receptor to the decidualizing uterus, the mouse can be used in future experiments as a much needed research tool to study other genes thought to be important for uterine decidualization using Cre/LoxP technology. In Specific Aim 2, we will test the functionality of the GPCR promoter to drive transgene expression. Findings derived from the successful completion of this research project will have broad application to the field of receptor signaling and will advance our understanding of maternal-embryo interactions.

描述（由申请人提供）：我们的实验室最近发现了一种新型鼠类 G 蛋白偶联受体 (GPCR)，它在胚胎植入时在蜕膜基质室中上调（7 倍）。 RT-PCR和原位杂交表明，新型GPCR在妊娠期间的表达模式在时间和空间上仅限于子宫间质，在其他组织/器官中不表达。使用人类蜕膜化基质细胞的研究表明，在人类蜕膜化过程中表达了功能对应物。因此，拟议的研究可能对人类怀孕产生影响。同样，已经确定肾素（一种通过血管紧张素原的蛋白水解裂解产生活性血流动力学肽的酶）在妊娠早期在子宫内膜中上调。我们的假设是，孤儿 GPCR 在功能上是正常妊娠所必需的，并且这种新受体可介导母体-胚胎界面上血管紧张素 (1-7) 诱导的血管舒张。在具体目标 1 中，我们建议在插入突变研究中证明受体的功能要求，其中将 cre 重组酶插入受体基因位点。将特别关注妊娠早期子宫血管动力学和前列腺素的产生。生成 GPCR-cre 小鼠品系的一个重要方面是，由于受体在蜕膜化子宫中的表达受到限制，因此小鼠可以在未来的实验中作为一种急需的研究工具来研究其他被认为对子宫发育重要的基因。使用 Cre/LoxP 技术进行子宫蜕膜化。在具体目标 2 中，我们将测试 GPCR 启动子驱动转基因表达的功能。该研究项目的成功完成所得出的结果将在受体信号传导领域具有广泛的应用，并将增进我们对母体与胚胎相互作用的理解。