Sphingosine-1-phosphate (S1P), a bioactive sphingolipid, regulates a variety of cellular functions such as proliferation, survival, chemotaxis etc. Recently, it has been shown that S1P is the high affinity ligand for the G-protein coupled receptor, EDG-1 (Endothelial Differentiation Gene-1). Importantly, a novel function of S1P/EDG-1 in blood vessel development and maturation has been proposed recently. For example, S1P promotes morphogenesis of endothelial cells in vitro and potentiates VEGF and FGF-induced angiogenesis in vivo. Furthermore, deletion of EDG-1 resulted in embryonic lethality due to the formation of immature vasculature. However, the molecular mechanisms underlying S1P/EDG-1 regulated angiogenesis remain elusive. Thus, our long-term goal is to understand the signaling and roles of this sphingolipid in endothelial functions. In this proposal, we will characterize signaling pathways regulated by the EDG-1 receptor. Initially, by utilizing the affinity purification procedure, a panel of cellular polypeptides was found to specifically associate with the third intracellular loop (i3 domain) of EDG-1 receptor. Among them, two protein kinases with apparent molecular masses of 120- and 56-kDa and a 21-kDa phosphoprotein were identified. We hypothesize that these EDG-1 associated kinases/polypeptides are critical for the S1 P/EDG-1 signaling, in particular in regulating the function of endothelial cells. Preliminary data suggest that pp120 kinase may be functionally important in EDG-1 signaling. Thus, we propose to prioritize and focus on determining the identity and functions of pp120 kinase in EDG-1 signaling in the context of vascular biology.
The research aims are I) purify and clone the pp120EDG-1 associated kinase, II) characterize the relevance of pp120 kinase in S1 P/EDG-1 signaling, III) study the functions of pp120 kinase in endothelial cells activation, and IV) determine the structure-function relationship of EDG-I-i3. The completion of these studies is anticipated to better our knowledge of molecular mechanisms underlying angiogenesis, which ultimately may lead to future therapeutic development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL071071-01A1
Application #
6682476
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Goldman, Stephen
Project Start
2003-07-01
Project End
2003-08-31
Budget Start
2003-07-01
Budget End
2003-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$285,500
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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