Interactions of LPA and prostaglandins in implantation

LPA 和前列腺素在着床过程中的相互作用

• 批准号: 7906588
• 负责人: JEROLD CHUN
• 金额: $ 0.72万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906588
• 关键词: Abbreviations; Acids; Address; Affinity; Blood; Blood Circulation; Cell Culture Techniques; Data; Defect; Embryo; Enzyme Gene; Enzymes; Female; Fertility; G-Protein-Coupled Receptors; Gene Expression; Genes; Genetic; Guanosine Triphosphate Phosphohydrolases; Heterotrimeric GTP-Binding Proteins; In Situ Hybridization; Individual; Indomethacin; Infertility; Knockout Mice; Link; Lysophosphatidic Acid Receptors; Lysophospholipid Receptors; Lysophospholipids; Metabolism; Molecular; Molecular Profiling; Mus; Pathway interactions; Pertussis Toxin; Phenotype; Phospholipase; Play; Process; Prostaglandin Production; Prostaglandin Receptor; Prostaglandins; Rattus; Receptor Activation; Receptor Gene; Regulation; Research Personnel; Role; Signal Transduction; System; Testing; Therapeutic; Time; Uterus; Work; base; cell type; gain of function; homologous recombination; hormone regulation; implantation; in vivo; loss of function; lysophosphatidic acid; natural Blastocyst Implantation; new therapeutic target; novel; pregnant; programs; receptor; reproductive; research study; rho; sphingosine 1-phosphate

A significant cause of infertility is disruption of normal embryo implantation. Molecular influences on this process have not been completely identified. A possible influence on implantation and female fertility might be via a bioactive lysophospholipid called lysophosphatidic acid (LPA). LPA activates G protein-coupled receptors (GPCRs) to exert its signaling effects. We have used homologous recombination to the third LPA receptor (called LPA3), and in preliminary studies, have observed reduced fertility attributed to delayed implantation and aberrant embryo spacing in mice lacking this receptor. Interestingly, the phenotype of LPA3- deficient female mice is remarkably similar to that seen in pregnant rats treated with indomethacin or mice deficient for cytosolic phospholipase A2a (cPLA2a), suggesting,a link between prostaglandins (PGs) and LPA signaling. In this proposal we will test the hypothesis that multiple lysophosphatidic acid (LPA) receptors influence embryo implantation. Three aims will be pursued. Aim 1 will determine roles for LPA signaling during implantation by examining LPA/LPA biosynthetic enzymes, and receptors expressed during implantation, with a focus on LPA3and LPA4. Aim 2 will determine the role of prostaglandins (PGs) on LPA signaling in implantation. Aim 3 will determine the mechanisms through which LPAs signaling interacts with PGs. As a pharmaceutically tractable molecule, lysophospholipid receptors could represent a new target for the therapeutic treatment of infertility. Work from this proposal will lay the groundwork towards realizing this possible therapeutic potential.

不孕症的一个重要原因是正常胚胎植入的破坏。分子影响 进程尚未完全确定。对着床和女性生育能力的可能影响可能是 通过一种称为溶血磷脂酸（LPA）的生物活性溶血磷脂。LPA激活G蛋白偶联 受体（GPCR）发挥其信号作用。我们对第三个LPA进行了同源重组 受体（称为LPA 3），并在初步研究中，观察到生育能力下降归因于延迟 在缺乏这种受体的小鼠中的植入和异常胚胎间隔。有趣的是，LPA 3- 缺乏吲哚美辛的雌性小鼠与用吲哚美辛治疗的怀孕大鼠或小鼠中观察到的非常相似 缺乏胞质磷脂酶A2 a（cPLA 2a），表明，在拟南芥素（PGs）和 LPA信令。 在这个建议中，我们将测试假设，多个溶血磷脂酸（LPA）受体影响 胚胎植入将追求三个目标。目标1将确定LPA信令在 通过检查LPA/LPA生物合成酶和植入期间表达的受体， 重点是LPA 3和LPA 4。目的2将确定洋地黄素（PGs）在LPA信号转导中的作用， 置入目的3将确定LPAs信号与PGs相互作用的机制。作为 溶血磷脂受体是一种药学上易处理的分子，可以代表一种新的靶点， 不孕症的治疗。这项建议的工作将为实现这一目标奠定基础 可能的治疗潜力。