In this merit extension proposal, we are requesting funds to extend the critical findings of SI P release and signaling in the vasculature. The first major aim ofthe research is to understand how SIP metabolic enzymes are regulated in the vascular endothelial cells to impact local (autocrine) as well as systemic SIP signaling. Secondly, we will fully explore the basic mechanisms and physiological impact ofthe SIP signaling system as a sensor of biomechanical shear stress on the endothelial cells. First, we hypothesize that Sphkl in the endothelial cell is primarily involved in local/autocrine signaling mode important for endothelial cell homeostatic and angiogenic reactions. We will derive an endothelial cell-specific inducible knockout of Sphkl and examine angiogenesis, endothelial cell patterning, pathologic angiogenesis, vascular permeability and inflammation. To examine the effect of systemic SI P, which is derived primarily by red blood cells, we will examine endothelial cell functions in the red blood cell-specific Sphkl knockout. Localized SI P signaling will be defined at the morphologic and ultrastructural level by immunolocalization studies in vivo as well as in primary cells. Second, we will explore the novel hypothesis that SIP metabolism and signaling constitutes a novel shear sensor/ signaling module in the endothelial cells. Mechanisms of how SIP is formed and released will be explored in detail in cultured vascular endothelial cells. In particular, we will focus on mechanisms that down regulate SIP lyase enzyme. Interestingly, laminar shear-induced downstream signaling mechanisms are critically dependent on SI PI receptor signaling, suggesting that this receptor is a sensor of physiological shear stress. We will explore this mechanism in detail using cultured endothelial cells. We anticipate that these experiments will allow us to better understand the role of sphingolipid metabolism and signaling in vascular endothelial cells. Since SIP receptor modulators have entered the therapeutic era, this knowledge is likely to have important clinical utility.

Public Health Relevance

SI P receptor modulators have entered the clinic;the first generation compound, called FTY720 has completed phase III studies for the control of autoimmune inflammation. This research will deepen our understanding of how SI P functions in essential cardiovascular functions important for normal health and how SIP system is dysregulated in cardiovascular disease in mouse models.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Olive, Michelle
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Garris, Christopher S; Blaho, Victoria A; Hla, Timothy et al. (2014) Sphingosine-1-phosphate receptor 1 signalling in T cells: trafficking and beyond. Immunology 142:347-53
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
Xiong, Yuquan; Hla, Timothy (2014) S1P control of endothelial integrity. Curr Top Microbiol Immunol 378:85-105
Mendelson, Karen; Evans, Todd; Hla, Timothy (2014) Sphingosine 1-phosphate signalling. Development 141:5-9
Blaho, Victoria A; Hla, Timothy (2014) An update on the biology of sphingosine 1-phosphate receptors. J Lipid Res 55:1596-1608
Montrose, David C; Scherl, Ellen J; Bosworth, Brian P et al. (2013) S1P? localizes to the colonic vasculature in ulcerative colitis and maintains blood vessel integrity. J Lipid Res 54:843-51
Mendelson, Karen; Zygmunt, Tomasz; Torres-Vazquez, Jesus et al. (2013) Sphingosine 1-phosphate receptor signaling regulates proper embryonic vascular patterning. J Biol Chem 288:2143-56
Garris, Christopher S; Wu, Linfeng; Acharya, Swati et al. (2013) Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nat Immunol 14:1166-72
Xiong, Yuquan; Lee, Hyeuk Jong; Mariko, Boubacar et al. (2013) Sphingosine kinases are not required for inflammatory responses in macrophages. J Biol Chem 288:32563-73
Hla, Timothy; Brinkmann, Volker (2011) Sphingosine 1-phosphate (S1P): Physiology and the effects of S1P receptor modulation. Neurology 76:S3-8

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