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Timothy Hla, PhD

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Hospital Title:
Investigator, Vascular Biology Program
Academic Title:
Chair and Professor, Patricia K. Donohoe, Department of Surgery, Harvard Medical School
Research Focus Area:
Lipid Mediators in Vascular Biology and DiseaseSphingosine 1 Phosphate SignalingGene Regulation in Vascular System
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Tim Hla's laboratory has been investigating the role of lipid mediators, sphingosine 1-phosphate (S1P) and prostanoids in vascular biology and disease. In the 1990s, we cloned the inducible cyclooxygenase (COX-2) and the first S1P receptor. Our work defined how the COX-2 pathway regulated angiogenesis, cancer and inflammatory disease. Recently, we are examining molecular mechanisms by which prostanoids interact with other lipid signaling systems to protect the vascular system and maintain health. Secondly, since our discovery of the S1P receptor we have been working on this novel signaling pathway to understand how it regulates vascular development and homeostasis and is dysregulated in vascular diseases. In addition, our work contributed to the development of S1P receptor inhibitors, which are being tested and used for treatment of a number of autoimmune diseases. Recently, we discovered that HDL-bound S1P activates vascular S1P receptors to inhibit vascular injury and disease. We also showed that proteins that bind to S1P, such as the HDL-bound apolipoprotein M (ApoM), direct specific biological functions of S1P by activating S1P receptors in unique ways. This mode of signaling, termed as, chaperone-dependent S1P signaling, may be a general mechanism for lipid mediators that are poorly soluble in water. We are also examining novel mechanisms of S1P metabolism, export into the extracellular environment, capture and signaling by novel chaperones, receptor-dependent signaling mechanisms and cross-talk with other cytokine, growth factor signaling pathways. Such mechanistic information is useful not only to achieve a deeper understanding of vascular health and disease but also to develop new therapeutic entities based on the S1P signaling system, In fact, our laboratory is developing novel small molecular as well as protein biotherapeutics with the potential to modulate diseases such as heart disease, stroke, autoimmune diseases, eye disease and cancer.

About the Researcher

Timothy Hla received his Ph.D. in biochemistry from The George Washington University. Following a post-doctoral training period in which he worked in the lab of Thomas Maciag, he started his laboratory at the Holland Laboratory at the American Red Cross, Rockville, MD. He was recruited to the University of Connecticut School of Medicine in Farmington, CT where he founded the research Center for Vascular Biology and was eventually promoted to Professor. In 2009, he was recruited as a Professor and Director of the Center for Vascular Biology at Weill Cornell Medicine, Cornell University. He moved his research program to Boston Children's Hospital in 2016 where he is appointed as an investigator at the Vascular Biology Program and Patricia K. Donohoe Professor of Surgery at the Harvard Medical School. Dr. Hla is an honorary member of the Japanese Biochemical Society, received an honorary M.D. degree from the Geothe University, Frankfurt, Germany and a MERIT award from the NHLBI, NIH in 2006.

Publications

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  1. Christensen PM, Liu CH, Swendeman SL, Obinata H, Qvortrup K, Nielsen LB, Hla T, Di Lorenzo A, Christoffersen C. Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1. FASEB J. 2016 Jun; 30(6):2351-9.
  2. Etemadi N, Chopin M, Anderton H, Tanzer MC, Rickard JA, Abeysekera W, Hall C, Spall SK, Wang B, Xiong Y, Hla T, Pitson SM, Bonder CS, Wong WW, Ernst M, Smyth GK, Vaux DL, Nutt SL, Nachbur U, Silke J. TRAF2 regulates TNF and NF-?B signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1. Elife. 2015 Dec 23; 4.
  3. Wagschal A, Najafi-Shoushtari SH, Wang L, Goedeke L, Sinha S, deLemos AS, Black JC, Ramírez CM, Li Y, Tewhey R, Hatoum I, Shah N, Lu Y, Kristo F, Psychogios N, Vrbanac V, Lu YC, Hla T, de Cabo R, Tsang JS, Schadt E, Sabeti PC, Kathiresan S, Cohen DE, Whetstine J, Chung RT, Fernández-Hernando C, Kaplan LM, Bernards A, Gerszten RE, Näär AM. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nat Med. 2015 Nov; 21(11):1290-7.
  4. Galvani S, Sanson M, Blaho VA, Swendeman SL, Obinata H, Conger H, Dahlbäck B, Kono M, Proia RL, Smith JD, Hla T. HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci Signal. 2015 Aug 11; 8(389):ra79.
  5. Mendelson K, Lan Y, Hla T, Evans T. Maternal or zygotic sphingosine kinase is required to regulate zebrafish cardiogenesis. Dev Dyn. 2015 Aug; 244(8):948-54.
  6. Li MH, Swenson R, Harel M, Jana S, Stolarzewicz E, Hla T, Shapiro LH, Ferrer F. Antitumor Activity of a Novel Sphingosine-1-Phosphate 2 Antagonist, AB1, in Neuroblastoma. J Pharmacol Exp Ther. 2015 Sep; 354(3):261-8.
  7. Blaho VA, Galvani S, Engelbrecht E, Liu C, Swendeman SL, Kono M, Proia RL, Steinman L, Han MH, Hla T. HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature. 2015 Jul 16; 523(7560):342-6.
  8. Lu YC, Chang SH, Hafner M, Li X, Tuschl T, Elemento O, Hla T. ELAVL1 modulates transcriptome-wide miRNA binding in murine macrophages. Cell Rep. 2014 Dec 24; 9(6):2330-43.
  9. Chang SH, Elemento O, Zhang J, Zhuang ZW, Simons M, Hla T. ELAVL1 regulates alternative splicing of eIF4E transporter to promote postnatal angiogenesis. Proc Natl Acad Sci U S A. 2014 Dec 23; 111(51):18309-14.
  10. Hla T, Kolesnick R. C16:0-ceramide signals insulin resistance. Cell Metab. 2014 Nov 4; 20(5):703-5.
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  12. Xiong Y, Yang P, Proia RL, Hla T. Erythrocyte-derived sphingosine 1-phosphate is essential for vascular development. J Clin Invest. 2014 Nov; 124(11):4823-8.
  13. Murakami K, Kohno M, Kadoya M, Nagahara H, Fujii W, Seno T, Yamamoto A, Oda R, Fujiwara H, Kubo T, Morita S, Nakada H, Hla T, Kawahito Y. Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model. PLoS One. 2014; 9(9):e106792.
  14. Giammanco A, Blanc V, Montenegro G, Klos C, Xie Y, Kennedy S, Luo J, Chang SH, Hla T, Nalbantoglu I, Dharmarajan S, Davidson NO. Intestinal epithelial HuR modulates distinct pathways of proliferation and apoptosis and attenuates small intestinal and colonic tumor development. Cancer Res. 2014 Sep 15; 74(18):5322-35.
  15. Camm J, Hla T, Bakshi R, Brinkmann V. Cardiac and vascular effects of fingolimod: mechanistic basis and clinical implications. Am Heart J. 2014 Nov; 168(5):632-44.
  16. Garris CS, Blaho VA, Hla T, Han MH. Sphingosine-1-phosphate receptor 1 signalling in T cells: trafficking and beyond. Immunology. 2014 Jul; 142(3):347-53.
  17. Li MH, Harel M, Hla T, Ferrer F. Induction of chemokine (C-C motif) ligand 2 by sphingosine-1-phosphate signaling in neuroblastoma. J Pediatr Surg. 2014 Aug; 49(8):1286-91.
  18. Chang SH, Hla T. Post-transcriptional gene regulation by HuR and microRNAs in angiogenesis. Curr Opin Hematol. 2014 May; 21(3):235-40.
  19. Thangada S, Shapiro LH, Silva C, Yamase H, Hla T, Ferrer FA. Treatment with the immunomodulator FTY720 (fingolimod) significantly reduces renal inflammation in murine unilateral ureteral obstruction. J Urol. 2014 May; 191(5 Suppl):1508-16.
  20. Li X, Lu YC, Dai K, Torregroza I, Hla T, Evans T. Elavl1a regulates zebrafish erythropoiesis via posttranscriptional control of gata1. Blood. 2014 Feb 27; 123(9):1384-92.
  21. Mendelson K, Evans T, Hla T. Sphingosine 1-phosphate signalling. Development. 2014 Jan; 141(1):5-9.
  22. Xiong Y, Hla T. S1P control of endothelial integrity. Curr Top Microbiol Immunol. 2014; 378:85-105.
  23. Garris CS, Wu L, Acharya S, Arac A, Blaho VA, Huang Y, Moon BS, Axtell RC, Ho PP, Steinberg GK, Lewis DB, Sobel RA, Han DK, Steinman L, Snyder MP, Hla T, Han MH. Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nat Immunol. 2013 Nov; 14(11):1166-72.
  24. Li MH, Hla T, Ferrer F. FTY720 inhibits tumor growth and enhances the tumor-suppressive effect of topotecan in neuroblastoma by interfering with the sphingolipid signaling pathway. Pediatr Blood Cancer. 2013 Sep; 60(9):1418-23.
  25. Hla T, Galvani S, Rafii S, Nachman R. S1P and the birth of platelets. J Exp Med. 2012 Nov 19; 209(12):2137-40.
  26. Torregroza I, Holtzinger A, Mendelson K, Liu TC, Hla T, Evans T. Regulation of a vascular plexus by gata4 is mediated in zebrafish through the chemokine sdf1a. PLoS One. 2012; 7(10):e46844.
  27. Obinata H, Hla T. Fine-tuning S1P therapeutics. Chem Biol. 2012 Sep 21; 19(9):1080-2.
  28. Jung B, Obinata H, Galvani S, Mendelson K, Ding BS, Skoura A, Kinzel B, Brinkmann V, Rafii S, Evans T, Hla T. Flow-regulated endothelial S1P receptor-1 signaling sustains vascular development. Dev Cell. 2012 Sep 11; 23(3):600-10.
  29. Takeshita H, Kitano M, Iwasaki T, Kitano S, Tsunemi S, Sato C, Sekiguchi M, Azuma N, Miyazawa K, Hla T, Sano H. Sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling regulates receptor activator of NF-?B ligand (RANKL) expression in rheumatoid arthritis. Biochem Biophys Res Commun. 2012 Mar 9; 419(2):154-9.
  30. Moolenaar WH, Hla T. SnapShot: Bioactive lysophospholipids. Cell. 2012 Jan 20; 148(1-2):378-378.e2.
  31. Obinata H, Hla T. Assessment of sphingosine-1-phosphate activity in biological samples by receptor internalization and adherens junction formation. Methods Mol Biol. 2012; 874:69-76.
  32. Blaho VA, Hla T. Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors. Chem Rev. 2011 Oct 12; 111(10):6299-320.
  33. Obinata H, Hla T. Sphingosine 1-phosphate in coagulation and inflammation. Semin Immunopathol. 2012 Jan; 34(1):73-91.
  34. Chang SH, Hla T. Gene regulation by RNA binding proteins and microRNAs in angiogenesis. Trends Mol Med. 2011 Nov; 17(11):650-8.
  35. Christoffersen C, Obinata H, Kumaraswamy SB, Galvani S, Ahnström J, Sevvana M, Egerer-Sieber C, Muller YA, Hla T, Nielsen LB, Dahlbäck B. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. Proc Natl Acad Sci U S A. 2011 Jun 7; 108(23):9613-8.
  36. Hla T, Brinkmann V. Sphingosine 1-phosphate (S1P): Physiology and the effects of S1P receptor modulation. Neurology. 2011 Feb 22; 76(8 Suppl 3):S3-8.
  37. Chun J, Hla T, Lynch KR, Spiegel S, Moolenaar WH. International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol Rev. 2010 Dec; 62(4):579-87.
  38. Thangada S, Khanna KM, Blaho VA, Oo ML, Im DS, Guo C, Lefrancois L, Hla T. Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics. J Exp Med. 2010 Jul 5; 207(7):1475-83.
  39. Hla T, Oo ML. Ramping up RANTES in the acute response to arterial injury. J Clin Invest. 2010 Jan; 120(1):90-2.
  40. Skoura A, Hla T. Regulation of vascular physiology and pathology by the S1P2 receptor subtype. Cardiovasc Res. 2009 May 1; 82(2):221-8.
  41. Hla T, Im DS. Cell biology. The ABCs of lipophile transport. Science. 2009 Feb 13; 323(5916):883-4.
  42. Li MH, Sanchez T, Milne GL, Morrow JD, Hla T, Ferrer F. S1P/S1P2 signaling induces cyclooxygenase-2 expression in Wilms tumor. J Urol. 2009 Mar; 181(3):1347-52.
  43. Skoura A, Hla T. Lysophospholipid receptors in vertebrate development, physiology, and pathology. J Lipid Res. 2009 Apr; 50 Suppl:S293-8.
  44. Sekiguchi M, Iwasaki T, Kitano M, Kuno H, Hashimoto N, Kawahito Y, Azuma M, Hla T, Sano H. Role of sphingosine 1-phosphate in the pathogenesis of Sjögren's syndrome. J Immunol. 2008 Feb 1; 180(3):1921-8.
  45. Subbaramaiah K, Hudis C, Chang SH, Hla T, Dannenberg AJ. EP2 and EP4 receptors regulate aromatase expression in human adipocytes and breast cancer cells. Evidence of a BRCA1 and p300 exchange. J Biol Chem. 2008 Feb 8; 283(6):3433-44.
  46. Skoura A, Sanchez T, Claffey K, Mandala SM, Proia RL, Hla T. Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina. J Clin Invest. 2007 Sep; 117(9):2506-16.
  47. Ghosh M, Wang H, Ai Y, Romeo E, Luyendyk JP, Peters JM, Mackman N, Dey SK, Hla T. COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARdelta activation. J Exp Med. 2007 Sep 3; 204(9):2053-61.
  48. Sanchez T, Skoura A, Wu MT, Casserly B, Harrington EO, Hla T. Induction of vascular permeability by the sphingosine-1-phosphate receptor-2 (S1P2R) and its downstream effectors ROCK and PTEN. Arterioscler Thromb Vasc Biol. 2007 Jun; 27(6):1312-8.
  49. Kono M, Belyantseva IA, Skoura A, Frolenkov GI, Starost MF, Dreier JL, Lidington D, Bolz SS, Friedman TB, Hla T, Proia RL. Deafness and stria vascularis defects in S1P2 receptor-null mice. J Biol Chem. 2007 Apr 6; 282(14):10690-6.
  50. Gonzalez-Cabrera PJ, Hla T, Rosen H. Mapping pathways downstream of sphingosine 1-phosphate subtype 1 by differential chemical perturbation and proteomics. J Biol Chem. 2007 Mar 9; 282(10):7254-64.
  51. Hla T, Feinmark SJ. A festschrift for J. Martyn Bailey, a biochemist extraordinaire. Prostaglandins Other Lipid Mediat. 2007 Feb; 83(1-2):154-7.
  52. Kohno M, Momoi M, Oo ML, Paik JH, Lee YM, Venkataraman K, Ai Y, Ristimaki AP, Fyrst H, Sano H, Rosenberg D, Saba JD, Proia RL, Hla T. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol Cell Biol. 2006 Oct; 26(19):7211-23.
  53. Lee JF, Zeng Q, Ozaki H, Wang L, Hand AR, Hla T, Wang E, Lee MJ. Dual roles of tight junction-associated protein, zonula occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity. J Biol Chem. 2006 Sep 29; 281(39):29190-200.
  54. Venkataraman K, Thangada S, Michaud J, Oo ML, Ai Y, Lee YM, Wu M, Parikh NS, Khan F, Proia RL, Hla T. Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient. Biochem J. 2006 Aug 1; 397(3):461-71.
  55. Michaud J, Kohno M, Proia RL, Hla T. Normal acute and chronic inflammatory responses in sphingosine kinase 1 knockout mice. FEBS Lett. 2006 Aug 21; 580(19):4607-12.
  56. Kitano M, Hla T, Sekiguchi M, Kawahito Y, Yoshimura R, Miyazawa K, Iwasaki T, Sano H, Saba JD, Tam YY. Sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 signaling in rheumatoid synovium: regulation of synovial proliferation and inflammatory gene expression. Arthritis Rheum. 2006 Mar; 54(3):742-53.
  57. Lee JF, Ozaki H, Zhan X, Wang E, Hla T, Lee MJ. Sphingosine-1-phosphate signaling regulates lamellipodia localization of cortactin complexes in endothelial cells. Histochem Cell Biol. 2006 Sep; 126(3):297-304.
  58. LaMontagne K, Littlewood-Evans A, Schnell C, O'Reilly T, Wyder L, Sanchez T, Probst B, Butler J, Wood A, Liau G, Billy E, Theuer A, Hla T, Wood J. Antagonism of sphingosine-1-phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization. Cancer Res. 2006 Jan 1; 66(1):221-31.
  59. Hla T. Immunology. Dietary factors and immunological consequences. Science. 2005 Sep 9; 309(5741):1682-3.
  60. Hla T. Genomic insights into mediator lipidomics. Prostaglandins Other Lipid Mediat. 2005 Sep; 77(1-4):197-209.
  61. Chang SH, Ai Y, Breyer RM, Lane TF, Hla T. The prostaglandin E2 receptor EP2 is required for cyclooxygenase 2-mediated mammary hyperplasia. Cancer Res. 2005 Jun 1; 65(11):4496-9.
  62. Jo E, Sanna MG, Gonzalez-Cabrera PJ, Thangada S, Tigyi G, Osborne DA, Hla T, Parrill AL, Rosen H. S1P1-selective in vivo-active agonists from high-throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate. Chem Biol. 2005 Jun; 12(6):703-15.
  63. Lepley D, Paik JH, Hla T, Ferrer F. The G protein-coupled receptor S1P2 regulates Rho/Rho kinase pathway to inhibit tumor cell migration. Cancer Res. 2005 May 1; 65(9):3788-95.
  64. Narko K, Zweifel B, Trifan O, Ristimäki A, Lane TF, Hla T. COX-2 inhibitors and genetic background reduce mammary tumorigenesis in cyclooxygenase-2 transgenic mice. Prostaglandins Other Lipid Mediat. 2005 May; 76(1-4):86-94.
  65. Chang SH, Liu CH, Wu MT, Hla T. Regulation of vascular endothelial cell growth factor expression in mouse mammary tumor cells by the EP2 subtype of the prostaglandin E2 receptor. Prostaglandins Other Lipid Mediat. 2005 May; 76(1-4):48-58.
  66. Heinonen M, Bono P, Narko K, Chang SH, Lundin J, Joensuu H, Furneaux H, Hla T, Haglund C, Ristimäki A. Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma. Cancer Res. 2005 Mar 15; 65(6):2157-61.
  67. Chae SS, Hla T. Inhibition of gene expression in vivo using multiplex siRNA. Methods Mol Biol. 2005; 309:197-203.
  68. Hla T. Physiological and pathological actions of sphingosine 1-phosphate. Semin Cell Dev Biol. 2004 Oct; 15(5):513-20.
  69. Knostman KA, Cho JY, Ryu KY, Lin X, McCubrey JA, Hla T, Liu CH, Di Carlo E, Keri R, Zhang M, Hwang DY, Kisseberth WC, Capen CC, Jhiang SM. Signaling through 3',5'-cyclic adenosine monophosphate and phosphoinositide-3 kinase induces sodium/iodide symporter expression in breast cancer. J Clin Endocrinol Metab. 2004 Oct; 89(10):5196-203.
  70. Chae SS, Paik JH, Furneaux H, Hla T. Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference. J Clin Invest. 2004 Oct; 114(8):1082-9.
  71. Paik JH, Skoura A, Chae SS, Cowan AE, Han DK, Proia RL, Hla T. Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev. 2004 Oct 1; 18(19):2392-403.
  72. Sanchez T, Hla T. Structural and functional characteristics of S1P receptors. J Cell Biochem. 2004 Aug 1; 92(5):913-22.
  73. Brinkmann V, Cyster JG, Hla T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant. 2004 Jul; 4(7):1019-25.
  74. Jang BC, Kim DH, Park JW, Kwon TK, Kim SP, Song DK, Park JG, Bae JH, Mun KC, Baek WK, Suh MH, Hla T, Suh SI. Induction of cyclooxygenase-2 in macrophages by catalase: role of NF-kappaB and PI3K signaling pathways. Biochem Biophys Res Commun. 2004 Apr 2; 316(2):398-406.
  75. Chae SS, Proia RL, Hla T. Constitutive expression of the S1P1 receptor in adult tissues. Prostaglandins Other Lipid Mediat. 2004 Jan; 73(1-2):141-50.
  76. Chang SH, Liu CH, Conway R, Han DK, Nithipatikom K, Trifan OC, Lane TF, Hla T. Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci U S A. 2004 Jan 13; 101(2):591-6.
  77. Sanchez T, Estrada-Hernandez T, Paik JH, Wu MT, Venkataraman K, Brinkmann V, Claffey K, Hla T. Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. J Biol Chem. 2003 Nov 21; 278(47):47281-90.
  78. Hla T. Signaling and biological actions of sphingosine 1-phosphate. Pharmacol Res. 2003 May; 47(5):401-7.
  79. Sengupta S, Jang BC, Wu MT, Paik JH, Furneaux H, Hla T. The RNA-binding protein HuR regulates the expression of cyclooxygenase-2. J Biol Chem. 2003 Jul 4; 278(27):25227-33.
  80. Inaba T, Sano H, Kawahito Y, Hla T, Akita K, Toda M, Yamashina I, Inoue M, Nakada H. Induction of cyclooxygenase-2 in monocyte/macrophage by mucins secreted from colon cancer cells. Proc Natl Acad Sci U S A. 2003 Mar 4; 100(5):2736-41.
  81. Donohue PJ, Richards CM, Brown SA, Hanscom HN, Buschman J, Thangada S, Hla T, Williams MS, Winkles JA. TWEAK is an endothelial cell growth and chemotactic factor that also potentiates FGF-2 and VEGF-A mitogenic activity. Arterioscler Thromb Vasc Biol. 2003 Apr 1; 23(4):594-600.
  82. Kluk MJ, Colmont C, Wu MT, Hla T. Platelet-derived growth factor (PDGF)-induced chemotaxis does not require the G protein-coupled receptor S1P1 in murine embryonic fibroblasts and vascular smooth muscle cells. FEBS Lett. 2003 Jan 2; 533(1-3):25-8.
  83. Ozaki H, Hla T, Lee MJ. Sphingosine-1-phosphate signaling in endothelial activation. J Atheroscler Thromb. 2003; 10(3):125-31.
  84. Bishop-Bailey D, Hla T, Warner TD. Intimal smooth muscle cells as a target for peroxisome proliferator-activated receptor-gamma ligand therapy. Circ Res. 2002 Aug 9; 91(3):210-7.
  85. Chun J, Goetzl EJ, Hla T, Igarashi Y, Lynch KR, Moolenaar W, Pyne S, Tigyi G. International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol Rev. 2002 Jun; 54(2):265-9.
  86. Ancellin N, Colmont C, Su J, Li Q, Mittereder N, Chae SS, Stefansson S, Liau G, Hla T. Extracellular export of sphingosine kinase-1 enzyme. Sphingosine 1-phosphate generation and the induction of angiogenic vascular maturation. J Biol Chem. 2002 Feb 22; 277(8):6667-75.
  87. Proia RL, Hla T. Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest. 2015 Apr; 125(4):1379-87.
  88. Obinata H, Gutkind S, Stitham J, Okuno T, Yokomizo T, Hwa J, Hla T. Individual variation of human S1P1 coding sequence leads to heterogeneity in receptor function and drug interactions. J Lipid Res. 2014 Dec; 55(12):2665-75.
  89. Xiong Y, Lee HJ, Mariko B, Lu YC, Dannenberg AJ, Haka AS, Maxfield FR, Camerer E, Proia RL, Hla T. Sphingosine kinases are not required for inflammatory responses in macrophages. J Biol Chem. 2013 Nov 08; 288(45):32563-73.
  90. Hla T, Dannenberg AJ. Sphingolipid signaling in metabolic disorders. Cell Metab. 2012 Oct 3; 16(4):420-34.
  91. Oo ML, Chang SH, Thangada S, Wu MT, Rezaul K, Blaho V, Hwang SI, Han DK, Hla T. Engagement of S1P1-degradative mechanisms leads to vascular leak in mice. J Clin Invest. 2011 Jun; 121(6):2290-300.
  92. Venkataraman K, Lee YM, Michaud J, Thangada S, Ai Y, Bonkovsky HL, Parikh NS, Habrukowich C, Hla T. Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circ Res. 2008 Mar 28; 102(6):669-76.
  93. Oo ML, Thangada S, Wu MT, Liu CH, Macdonald TL, Lynch KR, Lin CY, Hla T. Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem. 2007 Mar 23; 282(12):9082-9.
  94. Sanchez T, Thangada S, Wu MT, Kontos CD, Wu D, Wu H, Hla T. PTEN as an effector in the signaling of antimigratory G protein-coupled receptor. Proc Natl Acad Sci U S A. 2005 Mar 22; 102(12):4312-7.
  95. Subbaramaiah K, Howe LR, Bhardwaj P, Du B, Gravaghi C, Yantiss RK, Zhou XK, Blaho VA, Hla T, Yang P, Kopelovich L, Hudis CA, Dannenberg AJ. Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res (Phila). 2011 Mar; 4(3):329-46.
  96. Montrose DC, Scherl EJ, Bosworth BP, Zhou XK, Jung B, Dannenberg AJ, Hla T. S1P1 localizes to the colonic vasculature in ulcerative colitis and maintains blood vessel integrity. J Lipid Res. 2013 Mar; 54(3):843-51.
  97. Skoura A, Michaud J, Im DS, Thangada S, Xiong Y, Smith JD, Hla T. Sphingosine-1-phosphate receptor-2 function in myeloid cells regulates vascular inflammation and atherosclerosis. Arterioscler Thromb Vasc Biol. 2011 Jan; 31(1):81-5.
  98. Wang Z, Liu B, Wang P, Dong X, Fernandez-Hernando C, Li Z, Hla T, Li Z, Claffey K, Smith JD, Wu D. Phospholipase C beta3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice. J Clin Invest. 2008 Jan; 118(1):195-204.
  99. Li MH, Hla T, Ferrer F. Sphingolipid modulation of angiogenic factor expression in neuroblastoma. Cancer Prev Res (Phila). 2011 Aug; 4(8):1325-32.
  100. Ghosh M, Ai Y, Narko K, Wang Z, Peters JM, Hla T. PPARdelta is pro-tumorigenic in a mouse model of COX-2-induced mammary cancer. Prostaglandins Other Lipid Mediat. 2009 Apr; 88(3-4):97-100.
  101. Saba JD, Hla T. Point-counterpoint of sphingosine 1-phosphate metabolism. Circ Res. 2004 Apr 2; 94(6):724-34.
  102. Hla T, Venkataraman K, Michaud J. The vascular S1P gradient-cellular sources and biological significance. Biochim Biophys Acta. 2008 Sep; 1781(9):477-82.
  103. Estrada R, Zeng Q, Lu H, Sarojini H, Lee JF, Mathis SP, Sanchez T, Wang E, Kontos CD, Lin CY, Hla T, Haribabu B, Lee MJ. Up-regulating sphingosine 1-phosphate receptor-2 signaling impairs chemotactic, wound-healing, and morphogenetic responses in senescent endothelial cells. J Biol Chem. 2008 Oct 31; 283(44):30363-75.
  104. Li MH, Sanchez T, Yamase H, Hla T, Oo ML, Pappalardo A, Lynch KR, Lin CY, Ferrer F. S1P/S1P1 signaling stimulates cell migration and invasion in Wilms tumor. Cancer Lett. 2009 Apr 18; 276(2):171-9.
  105. Habrukowich C, Han DK, Le A, Rezaul K, Pan W, Ghosh M, Li Z, Dodge-Kafka K, Jiang X, Bittman R, Hla T. Sphingosine interaction with acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) regulates PP2A activity and cyclooxygenase (COX)-2 expression in human endothelial cells. J Biol Chem. 2010 Aug 27; 285(35):26825-31.
  106. Hla T. Plugging vascular leak by sphingosine kinase from bone marrow progenitor cells. Circ Res. 2009 Sep 25; 105(7):614-6.
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