Uterine Vascular Remodeling during Pregnancy

妊娠期子宫血管重塑

基本信息

批准号：
8680381
负责人：
James K Pru
金额：
$ 17.95万
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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8680381
关键词：
Angiotensinogen Attention Automobile Driving Biocompatible Materials Blood Pressure Blood Vessels Cells Clinical Code Communication Conceptions Cre-LoxP 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）：我们的实验室最近确定了一种新型的鼠G蛋白偶联受体（GPCR），该受体（GPCR）响应于植入的胚胎，在deciDualizatizatizatizational室中变得更调节（7倍）。 RT-PCR和原位杂交表明，新型GPCR在其表达模式上在妊娠期间对子宫的基质区室的表达模式受到限制，并且在其他组织/器官中未表达。使用人义大型基质细胞的研究表明，在人类决策过程中表达了功能性对应物。因此，拟议的研究可能会对人类怀孕产生影响。同样，已经确定，肾素是一种通过血管紧张素原的蛋白水解裂解产生活性血液动力学肽的酶，在妊娠期期间在子宫内膜中被上调。我们的假设是孤立的GPCR在正常妊娠功能上是需要的，并且这种新型受体用于介导母体 - 胚胎界面处的血管紧张素 - （1-7）诱导的血管舒张。在特定目标1中，我们建议在插入诱变研究中证明受体的功能需求，其中将CRE重组酶插入受体基因基因座中。在怀孕初期，将特别关注子宫血管动力学和前列腺素的产生。产生GPCR-CRE小鼠系的一个重要方面是，由于受体对叶解子宫的表达受到限制，可以在将来的实验中将小鼠用作急需的研究工具，以研究其他被认为对使用CRE/LOXP技术对子宫decIDAILIDIAL的基因。在特定的目标2中，我们将测试GPCR启动子的功能以驱动转基因表达。成功完成该研究项目的发现将在受体信号领域广泛应用，并将促进我们对孕产妇 - embryo相互作用的理解。