Photo of Timothy Hla,  PhD

Timothy Hla, PhD

Boston Children's Hospital

Boston Children's Hospital
Phone: (617) 919-2179


timothy.hla@childrens.harvard.edu

Timothy Hla, PhD

Boston Children's Hospital

EDUCATIONAL TITLES

  • Patricia K. Donahoe Professor, Surgery, Harvard Medical School
  • Investigator, Vascular Biology Program, Boston Children's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our laboratory has studied the role of lipid mediators in vascular system, inflammation, and cancer. We cloned the human cyclooxyrgenase-2 (COX-2) cDNA and showed that this gene is correlated with chronic inflammatory conditions and various cancers. We also developed a mouse model in which COX-2 is over expressed and showed that the induction of COX-2 is a major progression factor in tumorigenesis. A second area of research that we contributed is the area of sphingolipid signaling. My laboratory cloned and characterized the first sphingosine 1-phosphate (S1P) receptor and characterized the biology of this signaling system in vascular development, angiogenesis, inflammation, and vascular homeostasis. This receptor is critical for adaptive immune cell trafficking and inhibitors of this receptor have entered the clinic to treat autoimmune diseases. We are exploring the biology of this lipid mediator in vascular and immune systems, and developing novel therapeutic strategies based on the S1P pathway.

Publications

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  • Yanagida K, Engelbrecht E, Niaudet C, Jung B, Gaengel K, Holton K, Swendeman S, Liu CH, Levesque MV, Kuo A, Fu Z, Smith LEH, Betsholtz C, Hla T. Sphingosine 1-Phosphate Receptor Signaling Establishes AP-1 Gradients to Allow for Retinal Endothelial Cell Specialization. Dev Cell 2020; 52:779-793.e7. PubMed
  • Cartier A, Leigh T, Liu CH, Hla T. Endothelial sphingosine 1-phosphate receptors promote vascular normalization and antitumor therapy. Proc Natl Acad Sci U S A 2020; 117:3157-3166. PubMed
  • Pandey S, Banks KM, Kumar R, Kuo A, Wen D, Hla T, Evans T. Sphingosine kinases protect murine embryonic stem cells from sphingosine-induced cell cycle arrest. Stem Cells 2020. PubMed
  • Poganik JR, Long MJC, Disare MT, Liu X, Chang SH, Hla T, Aye Y. Post-transcriptional regulation of Nrf2-mRNA by the mRNA-binding proteins HuR and AUF1. FASEB J. 2019; 33:14636-14652. PubMed
  • Obinata H, Kuo A, Wada Y, Swendeman S, Liu CH, Blaho VA, Nagumo R, Sato K, Izumi T, Hla T. Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice. J Lipid Res 2019. PubMed
  • Hisano Y, Kono M, Cartier A, Engelbrecht E, Kano K, Kawakami K, Xiong Y, Piao W, Galvani S, Yanagida K, Kuo A, Ono Y, Ishida S, Aoki J, Proia RL, Bromberg JS, Inoue A, Hla T. Lysolipid receptor cross-talk regulates lymphatic endothelial junctions in lymph nodes. J Exp Med 2019; 216:1582-1598. PubMed
  • Obinata H, Hla T. Sphingosine 1-phosphate and inflammation. Int Immunol 2019. PubMed
  • Shi X, Wang W, Li J, Wang T, Lin Y, Huang S, Kuver A, Chen C, Hla T, Li X, Dai K. Sphingosine 1-phosphate receptor 1 regulates cell-surface localization of membrane proteins in endothelial cells. Biochim Biophys Acta Gen Subj 2019. PubMed
  • Xiong Y, Piao W, Brinkman CC, Li L, Kulinski JM, Olivera A, Cartier A, Hla T, Hippen KL, Blazar BR, Schwab SR, Bromberg JS. CD4 T cell sphingosine 1-phosphate receptor (S1PR)1 and S1PR4 and endothelial S1PR2 regulate afferent lymphatic migration. Sci Immunol 2019. PubMed
  • Cartier A, Hla T. Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science 2019. PubMed
  • Montrose DC, Zhou XK, McNally EM, Sue E, Wang H, Nishiguchi R, Verma A, Elemento O, Simpson KW, Yang P, Hla T, Dannenberg AJ. Colonoscopic-guided pinch biopsies in mice: A useful model for evaluating the roles of host and luminal factors in colonic inflammation. Am J Pathol 2018. PubMed
  • Hisano Y, Hla T. Bioactive lysolipids in cancer and angiogenesis. Pharmacol Ther 2018. PubMed
  • Kono M, Conlon EG, Lux SY, Yanagida K, Hla T, Proia RL. Bioluminescence imaging of G protein-coupled receptor activation in living mice. Nat Commun 2017; 8:1163. PubMed
  • 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; 58:1977-1987. PubMed
  • 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. PubMed
  • 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; 546:158-161. PubMed
  • 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. PubMed
  • Yanagida K, Hla T. Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. Annu Rev Physiol 2016; 79:67-91. PubMed
  • 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; 1:e87058. PubMed
  • 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; 30:2351-9. PubMed
  • 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; 523(7560):342-6.
  • Yanagida K, Hla T.. Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. 2016.
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