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: 7569939
• 负责人: JEROLD CHUN
• 金额: $ 37.42万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569939
• 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.

不孕的一个重要原因是正常胚胎植入的破坏。分子对此的影响 过程尚未完全确定。对着床和女性生育力的可能影响可能 通过称为溶血磷脂酸（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使用了同源重组 受体（称为 LPA3），并且在初步研究中，观察到生育力下降归因于延迟 缺乏这种受体的小鼠的植入和异常胚胎间距。有趣的是，LPA3-的表型 缺陷雌性小鼠与接受吲哚美辛治疗的怀孕大鼠或小鼠中观察到的情况非常相似 细胞质磷脂酶 A2a (cPLA2a) 缺陷，表明前列腺素 (PG) 和 LPA 信号。 在本提案中，我们将测试多种溶血磷脂酸 (LPA) 受体影响的假设 胚胎植入。将追求三个目标。目标 1 将确定 LPA 信号在 通过检查 LPA/LPA 生物合成酶和植入期间表达的受体来进行植入， 重点关注 LPA3 和 LPA4。目标 2 将确定前列腺素 (PG) 对 LPA 信号传导的作用 植入。目标 3 将确定 LPA 信号传导与 PG 相互作用的机制。作为一个 溶血磷脂受体是一种药物上易于处理的分子，可能代表一个新的靶标 不孕症的治疗。该提案的工作将为实现这一目标奠定基础 可能的治疗潜力。