Marion K. Gordon Associate Professor Rutgers University Department of Pharmacology and Toxicology EOHSI Piscataway. NJ 08854-8020 TEL: (732) 445-3751 FAX: (732) 445-0119 magordon@eohsi.rutgers.edu

Cell-matrix interactions; cell. developmental and molecular biology of extracellular matrix molecules

The laboratory of Dr. Marion Gordon is investigating cell-matrix interactions. as well as the cell. developmental and molecular biology of extracellular matrix molecules. One project studies epithelial cancers: EMMPRIN is a transmembrane molecule on the surface of epithelial-derived tumor cells that directs the neighboring fibroblasts to synthesize matrix metalloproteinases. allowing the tumors to alter the matrix and metastasize. In addition to examining how tumor cells regulate this molecule. the laboratory is attempting to determine the function of EMMPRIN in normal cells. Based on EMMPRIN's function in tumors. the transmembrane molecule is suspected to play a major role in normal matrix remodeling during development.

Another major project examines how extracellular matrix molecules establish the architecture of our tissues and organs during development and in pathology. A subset of collagens. the fibril-associated collagens (FACITs). modulate the properties of collagen fibrils. altering how the fibrils interact with adjacent fibrils. One of the lab's major goals is to understand the role of these bridging molecules in proper tissue architecture. In the developing eye. the cornea is at first opaque. and undergoes a compaction event that results in a transparent cornea. Dr. Gordon's work suggests that the FACIT molecule collagen XIV facilitates the compaction event by preventing the fusion of collagen fibrils. This would maintain fibrils in a lattice that can transmit light.

Misregulation of EMMPRIN and/or FACIT collagens is hypothesized to be important in disease states involving inappropriate synthesis and degradation of extracellular matrix. The laboratory is also investigating the involvement of collagens and EMMPRIN in the premature rupture of fetal membranes. in pulmonary hypertension. as well as in pulmonary and hepatic fibrosis. In each of these pathologies. FACIT collagen XII appears to temporarily stabilize new fibril structures until a permanent stabilization occurs. and a concomitant decrease in FACIT collagen XIV appears to allow type I collagen fibril fusions. Such fusions impair the resiliency of the tissues. Future work will examine the FACIT collagens in cystic fibrosis.

Selected Publications

Matsuo N, Tanaka S, Yoshioka H, Koch M, Gordon MK, Ramirez F. (2008) Collagen XXIV (Col24a1) gene expression is a specific marker of osteoblast differentiation and bone formation. Connect Tissue Res.49(2):68-75.

Chen LC, Laskin JD, Gordon MK, Laskin DL. (2008) Regulation of TREM expression in hepatic macrophages and endothelial cells during acute endotoxemia. Exp Mol Pathol. 84(2):145-55.

Veit G, Zimina EP, Franzke CW, Kutsch S, Siebolds U, Gordon MK, Bruckner-Tuderman L, Koch M. (2007) Shedding of collagen XXIII is mediated by furin and depends on the plasma membrane microenvironment. J Biol Chem. 282(37):27424-35.

Koch M. Veit G. Stickler S. Bhatt P. Kutsch S. Zhou P. Reinders E. Hahn RA. Song R. Burgeson RE. Gerecke DR. Mundlos S. Gordon MK. (2006) Expression of type XXIII collagen mRNA and protein. J Biol Chem. 281(30):21546-57.

Shakarjian MP. Bhatt P. Gordon MK. Chang YC. Casbohm SL. Rudge TL. Kiser RC. Sabourin CL. Casillas RP. Ohman-Strickland P. Riley DJ. Gerecke DR. (2006) Preferential expression of matrix metalloproteinase-9 in mouse skin after sulfur mustard exposure. J Appl Toxicol. 26(3):239-46.

Tzortzaki EG. Koutsopoulos AV. Dambaki KI. Lambiri I. Plataki M. Gordon MK. Gerecke DR. Siafakas NM. (2006) Active remodeling in idiopathic interstitial pneumonias: evaluation of collagen types XII and XIV. J Histochem Cytochem. 54(6):693-700.

Matsuo N. Tanaka S. Gordon MK. Koch M. Yoshioka H. Ramirez F. (2006) CREB-AP1 protein complexes regulate transcription of the collagen XXIV gene (Col24a1) in osteoblasts. J Biol Chem. 281(9):5445-52.

Kinzler WL. Smulian JC. Kistler CA. Hahn RA. Zhou P. Gordon MK. (2005) Extracellular matrix changes in the umbilical arteries of growth-restricted fetuses. Am J Obstet Gynecol. 192(4):1053-9.

Tzortzaki EG. Tischfield JA. Sahota A. Siafakas NM. Gordon MK. Gerecke DR. (2003) Expression of FACIT collagens XII and XIV during bleomycin-induced pulmonary fibrosis in mice. Anat Rec A Discov Mol Cell Evol Biol. 275(2):1073-80.

Gardner CR. Laskin JD. Dambach DM. Chiu H. Durham SK. Zhou P. Bruno M. Gerecke DR. Gordon MK. Laskin DL. (2003) Exaggerated hepatotoxicity of acetaminophen in mice lacking tumor necrosis factor receptor-1. Potential role of inflammatory mediators. Toxicol Appl Pharmacol. 192(2):119-30.

Koch M. Laub F. Zhou P. Hahn RA. Tanaka S. Burgeson RE. Gerecke DR. Ramirez F. Gordon MK. (2003) Collagen XXIV. a vertebrate fibrillar collagen with structural features of invertebrate collagens: selective expression in developing cornea and bone. J Biol Chem. 278(44):43236-44.

Meirowitz. N.B.. Smulian. J.C.. Hahn. R.A.. Zhou. P.. Shen-Schwarz. S.. Lambert. G.H.. Gerecke. D.R. and Gordon. M.K. Collagen mRNA expression in the human amniochorion in premature rupture of membranes. Am. J. Obstet. Gynecol. (2002) (in press).

Gardner. C.R.. Laskin. J.D.. Dambach. D.M.. Sacco. M.. Durham. S.K.. Bruno. M.K.. Cohen. S.D.. Gordon. M.K.. Gerecke. D.R.. Zhou. P.. and Laskin. D.L. (2002). Reduced hepatotoxicity of acetaminophen in mice lacking inducible nitric oxide synthase: potential role of tumor necrosis factor-alpha and interleukin-10. Toxicology and Applied Pharmacology 184:27- 35.

Gordon. M.K.. Hahn. R.A.. Zhou. P.. Bhatt. P.. Song. R.. Kistler. A.. Gerecke. D.R. and Koch. M. (2002). Characterization of a potential new fibrillar collagen. type XXIV. FASEB J.16: A359.

Koch. M.. Foley. J.E.. Hahn. R.A.. Zhou. P.. Burgeson. R.E.. Gerecke. D.R.and Gordon. M.K. "1(XX) collagen: a new member of the FACIT subfamily of collagens. J. Biol. Chem. 276:23120-23126. (2001).

Morio. L.A.. Chiu. H. Sprowles. K.A.. Zhou. P.. Heck. D.E.. Gordon. M.K. and Laskin. D.L. (2001) Distinct roles of tumor necrosis factor-" and nitric oxide in acute liver injury induced by carbon tetrachloride in mice. Toxicology and Applied Pharmacology 172:44-51.

Morio. L.A.. Chiu. H. Sprowles. K.A.. Zhou. P.. Heck. D.E.. Gordon. M.K. and Laskin. D.L. (2001) Distinct roles of tumor necrosis factor-" and nitric oxide in acute liver injury induced by carbon tetrachloride in mice. Toxicology and Applied Pharmacology 172:44-51.

Gordon. M.K.. Hahn. R.A.. Zhou. P.. Goyal. M.. Bhatt. P.. Heck. D.. Laskin. J.D.. Laskin. D.L.. McHugh. N.A.. Chen. G.. Tozzi. C.A.. Riley. D.J. and Gerecke. D.R. (2000) Type XII collagen and EMMPRIN in hypertensive pulmonary arteries. FASEB J. 14:A556.

Gerecke. D.R.. Hahn. R.. Zhang. P.. Heck. D.E.. Laskin. J.D.. Laskin. D.L.. Chen. G.. HcHugh. N.A.. Tozzi. C.A.. Riley. D.J.. and Gordon. M.K. (2000) Changes in collagen XII expression in hypertensive and recovering pulmonary artieries. Am. J. Respir. Crit. Care Med. 161:A444.

Young. B.B.. Gordon. M.K. and Birk. D.E. (2000) Characterization of type XIV collagen in developing chicken tendons: Expression is associated with assembly and growth of collagen fibrils. Dev. Dynamics 217:430-439.