Sphingosine 1-phosphate (S1P), a potent lipid mediator, acts through the G protein-coupled receptors to regulate vascular maturation, angiogenesis and immune cell trafficking. It is produced by the phosphorylation of sphingosine by the sphingosine kinase (Sphk)-1 and -2. Studies supported by this grant showed that Sphk isoenzymes are located at distinct subcellular compartments, Sphkla isoform is efficiently exported to the extracellular milieu as a functional kinase, a large S1P gradient is maintained between blood and interstitial compartments, Sphk2 is involved in the activation of the immunosuppressant drug FTY720, Sphk1 is upregulated in the intestinal tumor tissues and that intracellular metabolism of sphingosine by Sphk1 is critical for tumor cell proliferation in the ApcMin/+ model of intestinal neoplasia. These data support the emerging concept that Sphk isoenzymes function at different subcellular locations to precisely regulate the concentrations of sphingolipid mediators, thus establishing the S1P gradient between blood and interstitium. This proposal is based on the hypothesis that the function of Sphk isoforms is critical for the establishment of S1P gradient, receptor activation and the intracellular metabolism of sphingolipid mediators. Thus the specific aims are: 1. To determine the molecular basis for the establishment of the S1P gradient between blood and tissues. The hypothesis that extracellular export of Sphk1a isoform contributes to high plasma S1P levels will be tested in mouse models. Subcellular localization, activation-dependent translocation and receptor activation of Sphk will be characterized in live vascular cells using photoactivatable (PA)-GFP fusion proteins. 2. The S1P gradient is critical for receptor-dependent signaling in the vascular and immune cells. The cellular source of Sphk that contribute to high plasma levels will be determined. Whether high plasma S1P levels are required for optimal angiogenesis response will be tested in Sphk null mice. Contributions of hematopoietic and vascular cells in maintaining blood S1P levels and the angiogenic response will be investigated. 3. The Sphk1 gene is essential for the proliferative expansion of adenomatous polyps in the ApcMin/+ model of intestinal neoplasia. We will test the hypothesis that Sphk enzymes regulate intracellular sphingosine levels, which directly affect the cell-cycle machinery to inhibit cell proliferation. These studies are anticipated to further elucidate the logic of S1P signaling system in pathophysiology. This information is especially warranted as the S1P analog FTY720-P, an immunomodulator and an inhibitor of vascular permeability is undergoing phase III clinical trials. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL067330-07
Application #
7270618
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Goldman, Stephen
Project Start
2001-03-05
Project End
2011-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
7
Fiscal Year
2007
Total Cost
$359,270
Indirect Cost
Name
University of Connecticut
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
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Yanagida, Keisuke; Hla, Timothy (2017) Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. Annu Rev Physiol 79:67-91
Gazit, Salomé L; Mariko, Boubacar; Thérond, Patrice et al. (2016) Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock. Circ Res 119:e110-26
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Etemadi, Nima; Chopin, Michael; Anderton, Holly et al. (2015) TRAF2 regulates TNF and NF-?B signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1. Elife 4:
Cantalupo, Anna; Zhang, Yi; Kothiya, Milankumar et al. (2015) Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure. Nat Med 21:1028-1037
Blaho, Victoria A; Galvani, Sylvain; Engelbrecht, Eric et al. (2015) HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature 523:342-6
Xiong, Yuquan; Yang, Peiying; Proia, Richard L et al. (2014) Erythrocyte-derived sphingosine 1-phosphate is essential for vascular development. J Clin Invest 124:4823-8
Blaho, Victoria A; Hla, Timothy (2014) An update on the biology of sphingosine 1-phosphate receptors. J Lipid Res 55:1596-608
Mendelson, Karen; Evans, Todd; Hla, Timothy (2014) Sphingosine 1-phosphate signalling. Development 141:5-9

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