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Contributions to Science

1. My laboratory discovered the G protein-coupled receptor for sphingosine 1-phosphate (S1P) in the 1990s. At that time, S1P was widely considered as an intracellular second messenger. We cloned EDG-1 as an angiogenesis-inducible G protein-coupled receptor (GPCR) in 1990 and “de-orphaned” it as the S1P receptor in 1998. We also showed that activation of S1P receptors in endothelial cells results in adherens junction assembly, vascular stabilization and barrier integrity. Our work defined this lipid molecule as an extracellular lipid mediator that acts on GPCRs to induce various biological effects. S1P receptors are now well accepted to regulate critical functions in embryonic development, immunity, vascular and CNS functions. Our work also paved the way for the development of S1P receptor modulators, the first of which, Fingolimod/Gilenya is now approved for the treatment of multiple sclerosis, and several are being developed to control autoimmune diseases.
 
  • Hla T, Maciag T. An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors. J Biol Chem. 1990 Jun 5;265(16):9308-13. PubMed PMID: 2160972.
  • Lee MJ, Van Brocklyn JR, Thangada S, Liu CH, Hand AR, Menzeleev R, Spiegel S, Hla T. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science. 1998 Mar 6;279(5356):1552-5. PubMed PMID: 9488656.
  • Lee MJ, Thangada S, Claffey KP, Ancellin N, Liu CH, Kluk M, Volpi M, Sha'afi RI, Hla T. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell. 1999 Oct 29;99(3):301-12. PubMed PMID: 10555146.
  • 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. doi: 10.1016/j.devcel.2012.07.015. PubMed PMID: 22975328; PubMed Central PMCID: PMC3443394.
2. Our work contributed to the definition of biological and pathological actions of S1P in vascular and immune systems.  We showed that multiple cellular sources (endothelial cells and RBCs) are needed to maintain the high plasma S1P levels under homeostasis. Our work also developed the concept that receptor expression on the plasma membrane controls homeostatic and pathological actions of S1P. In addition, we defined molecular mechanisms that contribute to efficacy and adverse events associated with clinical use of S1P receptor inhibitors and discovered the novel chaperone for S1P in HDL (Apolipoprotein M). These efforts contributed to the clinical application of S1P receptor-targeted therapeutics and is stimulating current research on the biology of this lipid mediator and the development of novel cardiovascular S1PR-targeted therapeutics.
 
  • 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. doi: 10.1073/pnas.1103187108. Epub 2011 May 23. PubMed PMID: 21606363; PubMed Central PMCID: PMC3111292. (*co-senior authors)
  • Xiong Y, Yang P, Proia RL, Hla T. Erythrocyte-derived sphingosine 1-phosphate is essential for vascular development. J Clin Invest. 2014 Nov 3;124(11):4823-8.  doi: 10.1172/JCI77685. Epub 2014 Sep 24. PubMed PMID: 25250575.
  • 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. doi: 10.1038/nature14462. Epub 2015 Jun 8. PubMed PMID: 26053123; PubMed Central PMCID: PMC4506268.
  • Galvani S, Sanson M, Blaho VA, Swendeman SL, 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. doi: 10.1126/scisignal.aaa2581. PubMed PMID: 26268607.

3. My laboratory cloned the human cyclooxygenase-2 (COX-2) cDNA and showed that it is inducible not only by inflammatory mediators but also by angiogenic factors.  Our early work on the molecular biology of the prostaglandin biosynthetic pathway contributed to the development of selective COX-2 inhibitors by the pharmaceutical companies. Our work also contributed to our understanding of the role of prostaglandins in physiology and diseases (rheumatoid arthritis and cancer). For example, we were one of the initial proponents of the concept that regulation of expression of the COX enzyme rather than the regulation at the step of phospholipase A2 is the major regulatory step in prostaglandin synthesis. We also showed that COX-2 induction is one of the key steps in tumorigenesis and that COX-2 function regulates changes in the tumor microenvironment such as exaggerated angiogenesis. This work has implications in cancer prevention and the treatment of inflammatory diseases.

  • Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7384-8. PubMed PMID: 1380156; PubMed Central PMCID: PMC49714.
  • Crofford LJ, Wilder RL, Ristimäki AP, Sano H, Remmers EF, Epps HR, Hla T. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues. Effects of interleukin-1 beta, phorbol ester, and corticosteroids. J Clin Invest. 1994 Mar;93(3):1095-101. PubMed PMID: 8132748; PubMed Central PMCID: PMC294048.
  • Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, Haudenschild C, Lane TF, Hla T. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem. 2001 May 25;276(21):18563-9. Epub 2001 Mar 7. PubMed PMID: 11278747.
  • 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. Epub 2007 Aug 27. PubMed PMID: 17724132; PubMed Central PMCID: PMC2118704.
4. Our work on the COX-2 enzyme revealed that the regulation of expression of this inducible gene is at both transcriptional and post-transcriptional levels. Surprisingly, regulation of the COX-2 mRNA at the post-transcriptional level is accounts for the major fraction of the sustained prostaglandin synthesis seen in cytokine-activated cells. We showed that the COX-2 mRNA is stabilized by the RNA binding protein ELAVL1 (aka HuR). However, ELAVL1 interacts with the 3’UTR of many regulatory transcripts and promotes gene expression. To better understand the biological roles of ELAVL1, we developed a mouse model in which this RNA binding protein can be deleted inducibly and tissue specifically. We found that ELAVL1 regulates miRNA interaction of many transcripts involved in the regulation of angiogenesis in both macrophages and endothelial cells. In addition, ELAVL1 function in stem/ progenitor cells is essential for the survival of the rapidly proliferating populations. These efforts have led to a better understanding of how RNA binding proteins and miRNAs regulate gene expression and therefore control complex multicellular processes such as angiogenesis.
 
  • 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. doi: 10.1172/JCI38263. Epub 2009 Nov 2. PubMed PMID: 19884656; PubMed Central PMCID: PMC2786787.
  • 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. doi: 10.1074/jbc.M112.423871. Epub 2012 Dec 6. PubMed PMID: 23223443; PubMed Central PMCID: PMC3576095.
  • 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. doi: 10.1016/j.celrep.2014.11.030. Epub 2014 Dec 18. PubMedPMID: 25533351; PubMed Central PMCID: PMC4277505.
  • 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. doi: 10.1073/pnas.1412172111. Epub 2014 Nov 24. PubMed PMID: 25422430; PubMed Central PMCID: PMC4280608.