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Timothy Hla, PhD

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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Dr. Timothy 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.

For more information about current projects, please visit the Hla Lab Website.

Publications

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  1. Mendelson K, Pandey S, Hisano Y, Carellini F, Das B, Hla T, Evans T. The ceramide synthase 2b gene mediates genomic sensing and regulation of sphingosine Levels during zebrafish embryogenesis. Elife. 2017 Sep 28; 6.
  2. Singh RK, Haka AS, Brumfield A, Grosheva I, Bhardwaj P, Chin HF, Xiong Y, Hla T, Maxfield FR. Ceramide activation of RhoA/Rho kinase impairs actin polymerization during aggregated LDL catabolism. J Lipid Res. 2017 Oct; 58(10):1977-1987.
  3. Swendeman SL, Xiong Y, Cantalupo A, Yuan H, Burg N, Hisano Y, Cartier A, Liu CH, Engelbrecht E, Blaho V, Zhang Y, Yanagida K, Galvani S, Obinata H, Salmon JE, Sanchez T, Di Lorenzo A, Hla T. An engineered S1P chaperone attenuates hypertension and ischemic injury. Sci Signal. 2017 Aug 15; 10(492).
  4. 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. Correction: TRAF2 regulates TNF and NF-?B signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1. Elife. 2017 Jun 27; 6.
  5. Cantalupo A, Gargiulo A, Dautaj E, Liu C, Zhang Y, Hla T, Di Lorenzo A. S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure. Hypertension. 2017 Aug; 70(2):426-434.
  6. Galvani S, Hla T. Quality Versus Quantity: Making HDL Great Again. Arterioscler Thromb Vasc Biol. 2017 Jun; 37(6):1018-1019.
  7. Mendoza A, Fang V, Chen C, Serasinghe M, Verma A, Muller J, Chaluvadi VS, Dustin ML, Hla T, Elemento O, Chipuk JE, Schwab SR. Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature. 2017 06 01; 546(7656):158-161.
  8. Yanagida K, Liu CH, Faraco G, Galvani S, Smith HK, Burg N, Anrather J, Sanchez T, Iadecola C, Hla T. Size-selective opening of the blood-brain barrier by targeting endothelial sphingosine 1-phosphate receptor 1. Proc Natl Acad Sci U S A. 2017 Apr 25; 114(17):4531-4536.
  9. Ding BS, Liu CH, Sun Y, Chen Y, Swendeman SL, Jung B, Chavez D, Cao Z, Christoffersen C, Nielsen LB, Schwab SR, Rafii S, Hla T. HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver. JCI Insight. 2016 Dec 22; 1(21):e87058.
  10. Yanagida K, Hla T. Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. Annu Rev Physiol. 2017 Feb 10; 79:67-91.
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  12. Gazit SL, Mariko B, Thérond P, Decouture B, Xiong Y, Couty L, Bonnin P, Baudrie V, Le Gall SM, Dizier B, Zoghdani N, Ransinan J, Hamilton JR, Gaussem P, Tharaux PL, Chun J, Coughlin SR, Bachelot-Loza C, Hla T, Ho-Tin-Noé B, Camerer E. 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. 2016 Sep 30; 119(8):e110-26.
  13. 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. 2016 May 20; 291(21):11465.
  14. 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.
  15. 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.
  16. 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.
  17. Cantalupo A, Zhang Y, Kothiya M, Galvani S, Obinata H, Bucci M, Giordano FJ, Jiang XC, Hla T, Di Lorenzo A. Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure. Nat Med. 2015 Sep; 21(9):1028-1037.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. Hla T, Kolesnick R. C16:0-ceramide signals insulin resistance. Cell Metab. 2014 Nov 04; 20(5):703-5.
  26. 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.
  27. 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.
  28. 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.
  29. Huang C, Gonzalez DG, Cote CM, Jiang Y, Hatzi K, Teater M, Dai K, Hla T, Haberman AM, Melnick A. The BCL6 RD2 domain governs commitment of activated B cells to form germinal centers. Cell Rep. 2014 Sep 11; 8(5):1497-508.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. Chang SH, Hla T. Post-transcriptional gene regulation by HuR and microRNAs in angiogenesis. Curr Opin Hematol. 2014 May; 21(3):235-40.
  35. 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.
  36. Blaho VA, Hla T. An update on the biology of sphingosine 1-phosphate receptors. J Lipid Res. 2014 Aug; 55(8):1596-608.
  37. 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.
  38. Mendelson K, Evans T, Hla T. Sphingosine 1-phosphate signalling. Development. 2014 Jan; 141(1):5-9.
  39. Xiong Y, Hla T. S1P control of endothelial integrity. Curr Top Microbiol Immunol. 2014; 378:85-105.
  40. 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.
  41. 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.
  42. 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.
  43. Howe LR, Subbaramaiah K, Kent CV, Zhou XK, Chang SH, Hla T, Jakobsson PJ, Hudis CA, Dannenberg AJ. Genetic deletion of microsomal prostaglandin E synthase-1 suppresses mouse mammary tumor growth and angiogenesis. Prostaglandins Other Lipid Mediat. 2013 Oct; 106:99-105.
  44. 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.
  45. Mendelson K, Zygmunt T, Torres-Vázquez J, Evans T, Hla T. Sphingosine 1-phosphate receptor signaling regulates proper embryonic vascular patterning. J Biol Chem. 2013 Jan 25; 288(4):2143-56.
  46. Chang SH, Lu YC, Li X, Hsieh WY, Xiong Y, Ghosh M, Evans T, Elemento O, Hla T. Antagonistic function of the RNA-binding protein HuR and miR-200b in post-transcriptional regulation of vascular endothelial growth factor-A expression and angiogenesis. J Biol Chem. 2013 Feb 15; 288(7):4908-21.
  47. Hla T, Galvani S, Rafii S, Nachman R. S1P and the birth of platelets. J Exp Med. 2012 Nov 19; 209(12):2137-40.
  48. 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.
  49. Obinata H, Hla T. Fine-tuning S1P therapeutics. Chem Biol. 2012 Sep 21; 19(9):1080-2.
  50. Hla T, Dannenberg AJ. Sphingolipid signaling in metabolic disorders. Cell Metab. 2012 Oct 03; 16(4):420-34.
  51. 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.
  52. 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 09; 419(2):154-9.
  53. Moolenaar WH, Hla T. SnapShot: Bioactive lysophospholipids. Cell. 2012 Jan 20; 148(1-2):378-378.e2.
  54. 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.
  55. 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.
  56. Obinata H, Hla T. Sphingosine 1-phosphate in coagulation and inflammation. Semin Immunopathol. 2012 Jan; 34(1):73-91.
  57. Chang SH, Hla T. Gene regulation by RNA binding proteins and microRNAs in angiogenesis. Trends Mol Med. 2011 Nov; 17(11):650-8.
  58. 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 07; 108(23):9613-8.
  59. Li MH, Hla T, Ferrer F. Sphingolipid modulation of angiogenic factor expression in neuroblastoma. Cancer Prev Res (Phila). 2011 Aug; 4(8):1325-32.
  60. 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.
  61. 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.
  62. 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.
  63. 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.
  64. 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.
  65. 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 05; 207(7):1475-83.
  66. 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.
  67. Michaud J, Im DS, Hla T. Inhibitory role of sphingosine 1-phosphate receptor 2 in macrophage recruitment during inflammation. J Immunol. 2010 Feb 01; 184(3):1475-83.
  68. Hla T, Oo ML. Ramping up RANTES in the acute response to arterial injury. J Clin Invest. 2010 Jan; 120(1):90-2.
  69. Ghosh M, Aguila HL, Michaud J, Ai Y, Wu MT, Hemmes A, Ristimaki A, Guo C, Furneaux H, Hla T. Essential role of the RNA-binding protein HuR in progenitor cell survival in mice. J Clin Invest. 2009 Dec; 119(12):3530-43.
  70. Hla T. Plugging vascular leak by sphingosine kinase from bone marrow progenitor cells. Circ Res. 2009 Sep 25; 105(7):614-6.
  71. ter Braak M, Danneberg K, Lichte K, Liphardt K, Ktistakis NT, Pitson SM, Hla T, Jakobs KH, Meyer zu Heringdorf D. Galpha(q)-mediated plasma membrane translocation of sphingosine kinase-1 and cross-activation of S1P receptors. Biochim Biophys Acta. 2009 May; 1791(5):357-70.
  72. Skoura A, Hla T. Regulation of vascular physiology and pathology by the S1P2 receptor subtype. Cardiovasc Res. 2009 May 01; 82(2):221-8.
  73. Hla T, Im DS. Cell biology. The ABCs of lipophile transport. Science. 2009 Feb 13; 323(5916):883-4.
  74. 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.
  75. 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.
  76. 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.
  77. Skoura A, Hla T. Lysophospholipid receptors in vertebrate development, physiology, and pathology. J Lipid Res. 2009 Apr; 50 Suppl:S293-8.
  78. Li MH, Sanchez T, Pappalardo A, Lynch KR, Hla T, Ferrer F. Induction of antiproliferative connective tissue growth factor expression in Wilms' tumor cells by sphingosine-1-phosphate receptor 2. Mol Cancer Res. 2008 Oct; 6(10):1649-56.
  79. 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.
  80. Hla T, Venkataraman K, Michaud J. The vascular S1P gradient-cellular sources and biological significance. Biochim Biophys Acta. 2008 Sep; 1781(9):477-82.
  81. 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.
  82. 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 01; 180(3):1921-8.
  83. 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.
  84. 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 08; 283(6):3433-44.
  85. 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.
  86. 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 03; 204(9):2053-61.
  87. Lee YM, Venkataraman K, Hwang SI, Han DK, Hla T. A novel method to quantify sphingosine 1-phosphate by immobilized metal affinity chromatography (IMAC). Prostaglandins Other Lipid Mediat. 2007 Nov; 84(3-4):154-62.
  88. Soldi R, Mandinova A, Venkataraman K, Hla T, Vadas M, Pitson S, Duarte M, Graziani I, Kolev V, Kacer D, Kirov A, Maciag T, Prudovsky I. Sphingosine kinase 1 is a critical component of the copper-dependent FGF1 export pathway. Exp Cell Res. 2007 Sep 10; 313(15):3308-18.
  89. 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.
  90. 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 06; 282(14):10690-6.
  91. 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.
  92. 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 09; 282(10):7254-64.
  93. Hla T, Feinmark SJ. A festschrift for J. Martyn Bailey, a biochemist extraordinaire. Prostaglandins Other Lipid Mediat. 2007 Feb; 83(1-2):154-7.
  94. 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.
  95. 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.
  96. 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 01; 397(3):461-71.
  97. 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.
  98. Thompson B, Ancellin N, Fernandez SM, Hla T, Sha'afi RI. Protein kinase Calpha and sphingosine 1-phosphate-dependent signaling in endothelial cell. Prostaglandins Other Lipid Mediat. 2006 Jul; 80(1-2):15-27.
  99. Subbaramaiah K, Howe LR, Port ER, Brogi E, Fishman J, Liu CH, Hla T, Hudis C, Dannenberg AJ. HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence for a cyclooxygenase-2-dependent mechanism. Cancer Res. 2006 May 15; 66(10):5504-11.
  100. 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.
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  126. 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.
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  128. 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.
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  131. 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 04; 100(5):2736-41.
  132. 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 01; 23(4):594-600.
  133. 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 02; 533(1-3):25-8.
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  135. Jang BC, Muñoz-Najar U, Paik JH, Claffey K, Yoshida M, Hla T. Leptomycin B, an inhibitor of the nuclear export receptor CRM1, inhibits COX-2 expression. J Biol Chem. 2003 Jan 31; 278(5):2773-6.
  136. 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 09; 91(3):210-7.
  137. 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.
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