Interactions of LPA and prostaglandins in implantation

不孕不育的一个重要原因是正常胚胎着床受到干扰。分子对此的影响 进程尚未完全确定。对着床和女性生育力可能产生的影响 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(GPCRs)发挥其信号作用。我们已经对第三个LPA使用了同源重组 受体(称为LPA3)，并在初步研究中观察到由于延迟生育而导致的生育力下降 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，LPA3的表型- 缺陷雌性小鼠与用吲哚美辛治疗的怀孕大鼠或小鼠非常相似 缺乏胞浆磷脂酶A2a(CPLA2a)，提示前列腺素(PGs)与 LPA信令。 在这项提案中，我们将检验多个溶血磷脂酸(LPA)受体影响 胚胎植入。我们将追求三个目标。目标1将确定LPA信令在 通过检测LPA/LPA生物合成酶和在植入过程中表达的受体来进行植入， 重点介绍LPA3和LPA4。目标2将确定前列腺素(PG)在LPA信号转导通路中的作用 植入。目标3将确定LPA信号与PG相互作用的机制。作为一名 药物上易处理的分子，溶血磷脂受体可以代表一个新的靶点 不孕不育症的治疗。这项提案的工作将为实现这一目标奠定基础 可能的治疗潜力。

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.