Uterine Vascular Remodeling during Pregnancy

妊娠期子宫血管重塑

• 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
• 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

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(申请人提供)：我们的实验室最近发现了一种新的小鼠G蛋白偶联受体(GPCR)，它在胚胎植入后，在蜕膜间质中上调(7倍)。逆转录聚合酶链式反应和原位杂交结果表明，该基因在妊娠期间的表达模式仅限于子宫间质，而在其他组织/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一个功能对应的基因。因此，拟议的研究可能会对人类怀孕产生影响。同样，肾素，一种通过蛋白水解性裂解血管紧张素原产生活性血流动力学多肽的酶，在妊娠早期子宫内膜中上调。我们的假设是，孤儿的gpr是正常妊娠所必需的功能，并且这种新的受体在母体-胚胎界面介导血管紧张素-(1-7)诱导的血管扩张。在特定的目标1中，我们建议在插入突变研究中证明受体的功能要求，在该研究中，cre重组酶被插入到受体基因座中。将特别关注怀孕早期子宫血管动力学和前列腺素的产生。建立GPCR-cre小鼠系的一个重要方面是，由于受体对蜕膜子宫的表达受到限制，小鼠可以在未来的实验中用作亟需的研究工具，利用Cre/loxP技术研究其他被认为对子宫蜕膜形成重要的基因。在特定的目标2中，我们将测试GPCR启动子驱动转基因表达的功能。这一研究项目的成功完成将在受体信号转导领域产生广泛的应用，并将促进我们对母体-胚胎相互作用的理解。