Abstract

I propose to examine the inhibition of apoptosis by the lysophospholipid mediator, lysophosphatidic acid (LPA), via stimulation of specific members a family of GPCRs, known as the endothelial cell differentiation gene (EDG) receptors. The true cellular function of EDG receptors has yet to be clearly established. However, numerous studies have demonstrated the ability of LPA to elicit various biological responses. The goal of this study is to determine the initial components involved in the mechanism used by lysophospholipids to mediate the inhibition of apoptosis. Ultimately, the information obtained in this study will allow us to establish the pathway utilized by lysophospholipds to mediate this inhibition, and promote the design of pharmaceutical agents that could attenuate this inhibitory effect.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM064101-03
Application #
6657264
Study Section
Minority Programs Review Committee (MPRC)
Program Officer
Zlotnik, Hinda
Project Start
2002-09-10
Project End
2004-09-09
Budget Start
2003-09-10
Budget End
2004-09-09
Support Year
3
Fiscal Year
2003
Total Cost
$26,091
Indirect Cost

  Institution

Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904

  Publications

Foss Jr, Frank W; Snyder, Ashley H; Davis, Michael D et al. (2007) Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorg Med Chem 15:663-77
Bolick, David T; Srinivasan, Suseela; Kim, Kyu W et al. (2005) Sphingosine-1-phosphate prevents tumor necrosis factor-{alpha}-mediated monocyte adhesion to aortic endothelium in mice. Arterioscler Thromb Vasc Biol 25:976-81
Foss Jr, Frank W; Clemens, Jeremy J; Davis, Michael D et al. (2005) Synthesis, stability, and implications of phosphothioate agonists of sphingosine-1-phosphate receptors. Bioorg Med Chem Lett 15:4470-4
Davis, Michael D; Clemens, Jeremy J; Macdonald, Timothy L et al. (2005) Sphingosine 1-phosphate analogs as receptor antagonists. J Biol Chem 280:9833-41
Clemens, Jeremy J; Davis, Michael D; Lynch, Kevin R et al. (2005) Synthesis of 4(5)-phenylimidazole-based analogues of sphingosine-1-phosphate and FTY720: discovery of potent S1P1 receptor agonists. Bioorg Med Chem Lett 15:3568-72
Clemens, Jeremy J; Davis, Michael D; Lynch, Kevin R et al. (2004) Synthesis of benzimidazole based analogues of sphingosine-1-phosphate: discovery of potent, subtype-selective S1P4 receptor agonists. Bioorg Med Chem Lett 14:4903-6
Clemens, Jeremy J; Davis, Michael D; Lynch, Kevin R et al. (2003) Synthesis of para-alkyl aryl amide analogues of sphingosine-1-phosphate: discovery of potent S1P receptor agonists. Bioorg Med Chem Lett 13:3401-4
Brinkmann, Volker; Davis, Michael D; Heise, Christopher E et al. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277:21453-7