Gordon W. Laurie

Education

  • BS, McMaster University
  • MS, McGill University, Montreal, P.Q., CANADA
  • PhD, McGill University, Montreal, P.Q., CANADA

Primary Appointment

  • Associate Professor, Cell Biology

Contact

Research Interest(s)

Role of Prosecretory Mitogen 'Lacritin' in Epithelial Homeostasis, Secretion and Innate Defense

Research Description

My lab is interested in epithelial homeostasis, secretion and innate defense. We focus on the human prosecretory mitogen 'lacritin' that we discovered and named out of an unbiased screen for factors regulating ocular tearing (Sanghi et al, J Mol Biol '01). Tears are responsible for homeostasis of the surface of the eye and are essential for innate defense (Karnati et al, Exp Eye Res '13). Both functions are in whole or part contributed by lacritin (Wang et al, J Biol Chem ’13) or by cleavage potentiated fragments of lacritin (McKown et al, J Biol Chem, '14). Our exploration of lacritin cell targeting led to the discovery of a novel 'off/on' switch mechanism in which lacritin binding of the ubiquitous cell surface proteoglycan 'syndecan-1' requires prior removal of heparan sulfate chains by 'heparanase' (Ma et al, J Cell Biol '06; Zhang et al, J Biol Chem ‘13). Binding is mutually specified by lacritin's C-terminal mitogenic/prosurvival/prosecretory domain (Wang et al, J Cell Biol ’06) and syndecan-1's N-terminus via a highly selective mechanism requiring the hydrophobic GAGAL sequence, cleaved heparan sulfate and an N-terminal chondroitin sulfate chain in syndecan-1. Truncation and point mutational analysis has narrowed the active site in lacritin to an amphipathic alpha helix (Wang et al, J Cell Biol ’06; J Biol Chem ’13). Lacritin mitogenic and prosurvival signaling is rapid (within 20 sec) and likely initiated by a G-protein coupled receptor. Prosurvival signaling involves acetylation of FOXO3 to couple with autophagy mediator ATG101, as well as phosphorylation of FOXO1 to couple with ATG7. Thus in stressed epithelia, lacritin rapidly stimulates autophagy. This is transient and sufficient to remove stress-damaged proteins. Lacritin independently stimulates oxidative phosphorylation and mitochondrial fusion (Wang et al, J Biol Chem ’13). New areas of research are exploring: (i) the lacritin signaling receptor, (ii) lacritin mitochondrial signaling, (iii) direct or indirect targeting of sensory neurons, and (iv) lacritin’s cleavage-potentiated bactericidal activity. A UVa-based startup company was recently spun-off to take lacritin through phase II human clinical trials for ‘dry eye’, the most common eye disease. Twelve years ago, I organized the multi-institutional (UVa, James Madison, Eastern Virginia Medical School, Cornell, Johns Hopkins, UCSF, US Army at Fort Belvoir) Lacritin Consortium of collaborating labs. The Consortium has continuously met two to three times a year since 2002 to share data and explore new projects.

Selected Publications

  • Feng M, Baryla J, Liu H, Laurie G, McKown R, Ashki N, Bhayana D, Hutnik C. Cytoprotective effect of lacritin on human corneal epithelial cells exposed to benzalkonium chloride in vitro. Current eye research. 2014;39(6): 604-10. PMID: 24401093
  • McKown R, Coleman Frazier E, Zadrozny K, Deleault A, Raab R, Ryan D, Sia R, Lee J, Laurie G. A cleavage-potentiated fragment of tear lacritin is bactericidal. The Journal of biological chemistry. 2014;289(32): 22172-82. PMID: 24942736 | PMCID: PMC4139230
  • Vijmasi T, Chen F, Balasubbu S, Gallup M, McKown R, Laurie G, McNamara N. Topical administration of lacritin is a novel therapy for aqueous-deficient dry eye disease. Investigative ophthalmology & visual science. 2014;55(8): 5401-9. PMID: 25034600 | PMCID: PMC4148924
  • Karnati R, Laurie D, Laurie G. Lacritin and the tear proteome as natural replacement therapy for dry eye. Experimental eye research. 2013;117 39-52. PMID: 23769845 | PMCID: PMC3844047
  • McKown R, Raab R, Kachelries P, Caldwell S, Laurie G. Conserved regional 3' grouping of rare codons in the coding sequence of ocular prosecretory mitogen lacritin. Investigative ophthalmology & visual science. 2013;54(3): 1979-87. PMID: 23422824 | PMCID: PMC3604909
  • Velez V F, Romano J, McKown R, Green K, Zhang L, Raab R, Ryan D, Hutnik C, Frierson H, Laurie G. Tissue transglutaminase is a negative regulator of monomeric lacritin bioactivity. Investigative ophthalmology & visual science. 2013;54(3): 2123-32. PMID: 23425695 | PMCID: PMC3621506
  • Wang N, Zimmerman K, Raab R, McKown R, Hutnik C, Talla V, Tyler M, Lee J, Laurie G. Lacritin rescues stressed epithelia via rapid forkhead box O3 (FOXO3)-associated autophagy that restores metabolism. The Journal of biological chemistry. 2013;288(25): 18146-61. PMID: 23640897 | PMCID: PMC3689958
  • Zhang Y, Wang N, Raab R, McKown R, Irwin J, Kwon I, van Kuppevelt T, Laurie G. Targeting of heparanase-modified syndecan-1 by prosecretory mitogen lacritin requires conserved core GAGAL plus heparan and chondroitin sulfate as a novel hybrid binding site that enhances selectivity. The Journal of biological chemistry. 2013;288(17): 12090-101. PMID: 23504321 | PMCID: PMC3636894
  • Laurie D, Splan R, Green K, Still K, McKown R, Laurie G. Detection of prosecretory mitogen lacritin in nonprimate tears primarily as a C-terminal-like fragment. Investigative ophthalmology & visual science. 2012;53(10): 6130-6. PMID: 22871838 | PMCID: PMC3441044
  • Seifert K, Gandia N, Wilburn J, Bower K, Sia R, Ryan D, Deaton M, Still K, Vassilev V, Laurie G, McKown R. Tear lacritin levels by age, sex, and time of day in healthy adults. Investigative ophthalmology & visual science. 2012;53(10): 6610-6. PMID: 22918641 | PMCID: PMC3460390
  • Samudre S, Lattanzio F, Lossen V, Hosseini A, Sheppard J, McKown R, Laurie G, Williams P. Lacritin, a novel human tear glycoprotein, promotes sustained basal tearing and is well tolerated. Investigative ophthalmology & visual science. 2010;52(9): 6265-70. PMID: 21087963 | PMCID: PMC3176019
  • Zhang Y, McKown R, Raab R, Rapraeger A, Laurie G. Focus on molecules: syndecan-1. Experimental eye research. 2010;93(4): 329-30. PMID: 20599970 | PMCID: PMC2955988
  • Zhang Y, Ryan D, Bower K, Ilan N, Vlodavsky I, Laurie G. Focus on molecules: heparanase. Experimental eye research. 2010;91(4): 476-7. PMID: 20478306 | PMCID: PMC2933305
  • Laurie G, Olsakovsky L, Conway B, McKown R, Kitagawa K, Nichols J. Dry eye and designer ophthalmics. Optometry and vision science : official publication of the American Academy of Optometry. 2008;85(8): 643-52. PMID: 18677231 | PMCID: PMC2815326
  • McKown R, Wang N, Raab R, Karnati R, Zhang Y, Williams P, Laurie G. Lacritin and other new proteins of the lacrimal functional unit. Experimental eye research. 2008;88(5): 848-58. PMID: 18840430 | PMCID: PMC2712882
  • Ma P, Wang N, McKown R, Raab R, Laurie G. Focus on molecules: lacritin. Experimental eye research. 2007;86(3): 457-8. PMID: 17412322 | PMCID: PMC2277456
  • Ma P, Beck S, Raab R, McKown R, Coffman G, Utani A, Chirico W, Rapraeger A, Laurie G. Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin. The Journal of cell biology. 2006;174(7): 1097-106. PMID: 16982797 | PMCID: PMC1666580
  • Wang J, Wang N, Xie J, Walton S, McKown R, Raab R, Ma P, Beck S, Coffman G, Hussaini I, Laurie G. Restricted epithelial proliferation by lacritin via PKCalpha-dependent NFAT and mTOR pathways. The Journal of cell biology. 2006;174(5): 689-700. PMID: 16923831 | PMCID: PMC1761701
  • Ozyildirim A, Wistow G, Gao J, Wang J, Dickinson D, Frierson H, Laurie G. The lacrimal gland transcriptome is an unusually rich source of rare and poorly characterized gene transcripts. Investigative ophthalmology & visual science. 2005;46(5): 1572-80. PMID: 15851553
  • Wang J, Laurie G. Organogenesis of the exocrine gland. Developmental biology. 2004;273(1): 1-22. PMID: 15302594
  • Kumar R, Huebner A, Laurie G. Genetic separation of the human lacritin gene ("LACRT") and triple A (Allgrove) syndrome on 12q13. Advances in experimental medicine and biology. 2003;506 167-74. PMID: 12613904
  • Faisal Khan K, Laurie G, McCaffrey T, Falcone D. Exposure of cryptic domains in the alpha 1-chain of laminin-1 by elastase stimulates macrophages urokinase and matrix metalloproteinase-9 expression. The Journal of biological chemistry. 2002;277(16): 13778-86. PMID: 11827968
  • Kumar R, Eastwood A, Brown M, Laurie G. Human genome search in celiac disease: mutated gliadin T-cell-like epitope in two human proteins promotes T-cell activation. Journal of molecular biology. 2002;319(3): 593-602. PMID: 12054857
  • Edlund M, Miyamoto T, Sikes R, Ogle R, Laurie G, Farach-Carson M, Otey C, Zhau H, Chung L. Integrin expression and usage by prostate cancer cell lines on laminin substrata. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 2001;12(2): 99-107. PMID: 11243469
  • Pogány G, Timár F, Oláh J, Harisi R, Polony G, Paku S, Bocsi J, Jeney A, Laurie G. Role of the basement membrane in tumor cell dormancy and cytotoxic resistance. Oncology. 2001;60(3): 274-81. PMID: 11340380
  • Sanghi S, Kumar R, Lumsden A, Dickinson D, Klepeis V, Trinkaus-Randall V, Frierson H, Laurie G. cDNA and genomic cloning of lacritin, a novel secretion enhancing factor from the human lacrimal gland. Journal of molecular biology. 2001;310(1): 127-39. PMID: 11419941
  • Kumar R, Lumsden A, Ciclitira P, Ellis H, Laurie G. Human genome search in celiac disease using gliadin cDNA as probe. Journal of molecular biology. 2000;300(5): 1155-67. PMID: 10903861
  • Sanghi S, Kumar R, Walton S, Laurie G. Quantitation of rat lacrimal secretion: a novel sandwich ELISA with high sensitivity. Experimental eye research. 2000;70(5): 651-8. PMID: 10870523
  • Asrani A, Lumsden A, Kumar R, Laurie G. Gene cloning of BM180, a lacrimal gland enriched basement membrane protein with a role in stimulated secretion. Advances in experimental medicine and biology. 1998;438 49-54. PMID: 9634862
  • Chen L, Glass J, Walton S, Laurie G. Role of laminin-1, collagen IV, and an autocrine factor(s) in regulated secretion by lacrimal acinar cells. The American journal of physiology. 1998;275(1): C278-84. PMID: 9688859
  • Scholz E, Pogany G, Ganzler K, Laurie G. Characterization of a basement membrane protein (BM180) using capillary electrophoresis. Journal of capillary electrophoresis. 1998;4(6): 287-92. PMID: 9827419
  • Chen L, Shick V, Matter M, Laurie S, Ogle R, Laurie G. Laminin E8 alveolarization site: heparin sensitivity, cell surface receptors, and role in cell spreading. The American journal of physiology. 1997;272(3): L494-503. PMID: 9124607
  • Caniggia I, Liu J, Han R, Wang J, Tanswell A, Laurie G, Post M. Identification of receptors binding fibronectin and laminin on fetal rat lung cells. The American journal of physiology. 1996;270(3): L459-68. PMID: 8638739
  • Laurie G, Glass J, Ogle R, Stone C, Sluss J, Chen L. "BM180": a novel basement membrane protein with a role in stimulus-secretion coupling by lacrimal acinar cells. The American journal of physiology. 1996;270(6): C1743-50. PMID: 8764158
  • Matter M, Laurie G. A putative sub-10-kDa basement membrane activity required for lung alveolar formation in vitro. The American journal of physiology. 1996;271(3): L489-94. PMID: 8843800
  • Chakravarti S, Horchar T, Jefferson B, Laurie G, Hassell J. Recombinant domain III of perlecan promotes cell attachment through its RGDS sequence. The Journal of biological chemistry. 1995;270(1): 404-9. PMID: 7814401
  • Laurie G, Glass J, Ogle R. Basement membrane modulation of stimulated secretion by lacrimal acinar cells. Advances in experimental medicine and biology. 1994;350 37-44. PMID: 8030505
  • Laurie G, Stone C, Glass J. Serum-free primary culture of harderian acinar cells. Experimental eye research. 1994;58(3): 375-8. PMID: 8174657
  • Matter M, Laurie G. A novel laminin E8 cell adhesion site required for lung alveolar formation in vitro. The Journal of cell biology. 1994;124(6): 1083-90. PMID: 8132708 | PMCID: PMC2119975
  • Stone C, Laurie G. Cell-specific expression of LBP-32 mRNA in retina and other locations of newborn mouse eye as revealed by in situ hybridization. Current eye research. 1992;11(9): 923-7. PMID: 1424732
  • Laurie G, Stone C, Yamada Y. Elevated 32-kDa LBP and low laminin mRNA expression in developing mouse cerebrum. Differentiation; research in biological diversity. 1991;46(3): 173-9. PMID: 1833253
  • Stone C, Laurie G. Cellular expression of collagen IV mRNA in eye. Experimental eye research. 1991;53(5): 677-80. PMID: 1743266
  • Taub M, Laurie G, Martin G, Kleinman H. Altered basement membrane protein biosynthesis by primary cultures of cpk/cpk mouse kidney. Kidney international. 1990;37(4): 1090-7. PMID: 2160557
  • Laurie G, Horikoshi S, Killen P, Segui-Real B, Yamada Y. In situ hybridization reveals temporal and spatial changes in cellular expression of mRNA for a laminin receptor, laminin, and basement membrane (type IV) collagen in the developing kidney. The Journal of cell biology. 1989;109(3): 1351-62. PMID: 2527859 | PMCID: PMC2115755
  • Ebihara I, Killen P, Laurie G, Huang T, Yamada Y, Martin G, Brown K. Altered mRNA expression of basement membrane components in a murine model of polycystic kidney disease. Laboratory investigation; a journal of technical methods and pathology. 1988;58(3): 262-9. PMID: 3279260
  • Laurie G, Inoue S, Bing J, Hassell J. Visualization of the large heparan sulfate proteoglycan from basement membrane. The American journal of anatomy. 1988;181(3): 320-6. PMID: 2452565
  • Chandrasekhar S, Laurie G, Cannon F, Martin G, Kleinman H. In vitro regulation of cartilage matrix assembly by a Mr 54,000 collagen-binding protein. Proceedings of the National Academy of Sciences of the United States of America. 1986;83(14): 5126-30. PMID: 3014533 | PMCID: PMC323903
  • Hassell J, Noonan D, Ledbetter S, Laurie G. Biosynthesis and structure of the basement membrane proteoglycan containing heparan sulphate side-chains. Ciba Foundation symposium. 1986;124 204-22. PMID: 2949947
  • Kleinman H, McGarvey M, Hassell J, Star V, Cannon F, Laurie G, Martin G. Basement membrane complexes with biological activity. Biochemistry. 1986;25(2): 312-8. PMID: 2937447
  • Laurie G, Bing J, Kleinman H, Hassell J, Aumailley M, Martin G, Feldmann R. Localization of binding sites for laminin, heparan sulfate proteoglycan and fibronectin on basement membrane (type IV) collagen. Journal of molecular biology. 1986;189(1): 205-16. PMID: 2946868
  • Lack of heparan sulfate proteoglycan in a discontinuous and irregular placental basement membrane. Developmental biology. 1985;108(2): 299-309. PMID: 2934285
  • Bohnsack J, Tenner A, Laurie G, Kleinman H, Martin G, Brown E. The C1q subunit of the first component of complement binds to laminin: a mechanism for the deposition and retention of immune complexes in basement membrane. Proceedings of the National Academy of Sciences of the United States of America. 1985;82(11): 3824-8. PMID: 2987948 | PMCID: PMC397880
  • Kleinman H, Cannon F, Laurie G, Hassell J, Aumailley M, Terranova V, Martin G, DuBois-Dalcq M. Biological activities of laminin. Journal of cellular biochemistry. 1985;27(4): 317-25. PMID: 3889019
  • Laurie G, Leblond C. Basement membrane nomenclature. Nature. 1985;313(6000): 272. PMID: 3969140
  • Laurie G, Leblond C, Inoue S, Martin G, Chung A. Fine structure of the glomerular basement membrane and immunolocalization of five basement membrane components to the lamina densa (basal lamina) and its extensions in both glomeruli and tubules of the rat kidney. The American journal of anatomy. 1984;169(4): 463-81. PMID: 6375342
  • Inoué S, Leblond C, Laurie G. Ultrastructure of Reichert's membrane, a multilayered basement membrane in the parietal wall of the rat yolk sac. The Journal of cell biology. 1983;97(5): 1524-37. PMID: 6226670 | PMCID: PMC2112687
  • Laurie G, Leblond C. What is known of the production of basement membrane components. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 1983;31(1): 159-63. PMID: 6186721
  • Laurie G, Leblond C, Martin G. Light microscopic immunolocalization of type IV collagen, laminin, heparan sulfate proteoglycan, and fibronectin in the basement membranes of a variety of rat organs. The American journal of anatomy. 1983;167(1): 71-82. PMID: 6346854
  • Laurie G, Leblond C. Intracellular localization of basement membrane precursors in the endodermal cells of the rat parietal yolk sac. I. Ultrastructure and phosphatase activity of endodermal cells. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 1982;30(10): 973-82. PMID: 6290565
  • Laurie G, Leblond C, Martin G. Intracellular localization of basement membrane precursors in the endodermal cells of the rat parietal yolk sac. II. Immunostaining for type IV collagen and its precursors. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 1982;30(10): 983-90. PMID: 6752264
  • Laurie G, Leblond C, Martin G. Localization of type IV collagen, laminin, heparan sulfate proteoglycan, and fibronectin to the basal lamina of basement membranes. The Journal of cell biology. 1982;95(1): 340-4. PMID: 6216257 | PMCID: PMC2112347
  • Laurie G, Leblond C, Martin G, Silver M. Intracellular localization of basement membrane precursors in the endodermal cells of the rat parietal yolk sac. III. Immunostaining for laminin and its precursors. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 1982;30(10): 991-8. PMID: 6752265