Abstract

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. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD050685-02
Application #
7228875
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Yoshinaga, Koji
Project Start
2006-05-01
Project End
2011-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$374,557
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Funke, Manuela; Zhao, Zhenwen; Xu, Yan et al. (2012) The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury. Am J Respir Cell Mol Biol 46:355-64
Mutoh, Tetsuji; Rivera, Richard; Chun, Jerold (2012) Insights into the pharmacological relevance of lysophospholipid receptors. Br J Pharmacol 165:829-44
Ye, Xiaoqin; Diao, Honglu; Chun, Jerold (2012) 11-deoxy prostaglandin F(2?), a thromboxane A2 receptor agonist, partially alleviates embryo crowding in Lpar3((-/-)) females. Fertil Steril 97:757-63
Ye, Xiaoqin; Herr, Deron R; Diao, Honglu et al. (2011) Unique uterine localization and regulation may differentiate LPA3 from other lysophospholipid receptors for its role in embryo implantation. Fertil Steril 95:2107-13, 2113.e1-4
Herr, Keira Joann; Herr, Deron R; Lee, Chang-Wook et al. (2011) Stereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA1) signaling. Proc Natl Acad Sci U S A 108:15444-9
Zhao, Chenqi; Sardella, Anne; Chun, Jerold et al. (2011) TNF-alpha promotes LPA1- and LPA3-mediated recruitment of leukocytes in vivo through CXCR2 ligand chemokines. J Lipid Res 52:1307-18
Diao, Honglu; Aplin, John D; Xiao, Shuo et al. (2011) Altered spatiotemporal expression of collagen types I, III, IV, and VI in Lpar3-deficient peri-implantation mouse uterus. Biol Reprod 84:255-65
Lin, Songbai; Lee, Sei-Jung; Shim, Hyunsuk et al. (2010) The absence of LPA receptor 2 reduces the tumorigenesis by ApcMin mutation in the intestine. Am J Physiol Gastrointest Liver Physiol 299:G1128-38
Lin, Songbai; Yeruva, Sunil; He, Peijian et al. (2010) Lysophosphatidic acid stimulates the intestinal brush border Na(+)/H(+) exchanger 3 and fluid absorption via LPA(5) and NHERF2. Gastroenterology 138:649-58
Chun, Jerold; Hla, Timothy; Lynch, Kevin R et al. (2010) International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol Rev 62:579-87

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