The cells in all organs of the body are supported by an extracellular matrix which is instructional to the cells. Components of the matrix tell the cells whether they should proliferate, migrate, apoptose or differentiate. The overall interest of the laboratory is to understand how cells control the expression of extracellular matrix genes, setting up an “inside out” and “outside in” communication system that results in normal, healthy functional organs, capable of an response to injury that is appropriate and not pathological.

Funded by an RO1 grant from the National Eye Institute of NIH to study specialized collagens in the cornea, the Gordon laboratory examines how the extracellular matrix contributes to the 3 major functions of the cornea: performing 80% of the light refraction needed to focus images on the retina, maintaining a transparent structure so that maximal light is transmitted to the photoreceptors, and setting up a flexible, but tough, barrier that protects the internal light focusing and detecting apparatus from injury. In addition, the laboratory is trying to establish a culture system model where immortalized corneal epithelial cells behave phenotypically like the in vivo corneal epithelium. Current models reported in the literature use cells that act as if they are already injured, expressing inflammatory mediators and collagens typical of wounded corneas. Our result show that use of particular extracellular matrix components in the cultures can prevent the expression of COX-2 and other markers of injury.

Another interest of the Gordon laboratory is the pathological misregulation of collagen genes that occurs when elastic tissues become non-compliant. In collaboration with Dr. Donald Gerecke and Dr. David Riley, a reversible rat model of pulmonary hypertension has shown that the cells in the arterial walls lose the ability to control collagen fibril diameter, resulting in a non-compliant vessel. However, appropriate environmental conditions permit the hypertensive matrix to be remodeled back to normal. These biological events are being compared to a non-reversible model of lung fibrosis (bleomycin-treated mice), where collagen fibril diameter control is lost, and cannot be re-established. In both pathologies, the expression of a specialized collagen, type XIV, which is a fibril diameter regulator, does not keep pace with the expression of fibrillar collagen I. The resulting fibrillar structure is too thick, impairing tissue elasticity. The lab would like to understand why the arterial cells are able to turn on genes that remodel their non-compliant matrix while the lung cells are not. The ultimate goal is to manipulate the lung cells so they are forced to remodel their matrix and re-establish tissue compliance.

Metastatic cancer involves the misregulation of extracellular matrix genes favoring cell mobility and migration. The Gordon laboratory studies two specific molecules upregulated in metastatic cancer cells: EMMPRIN and collagen XXIII. Both are transmembrane molecules on the surface of epithelial-derived tumors, and both are greatly up-regulated when the tumors are highly metastatic. By being shed from the tumor surface, EMMPRIN induces neighboring fibroblasts to synthesize matrix metalloproteinases, facilitating metastasis. Because collagen XXIII is a newly discovered molecule, its function is not yet known. However, its expression is graded in prostate cancer cells of varying metastatic potential. The research goal is to determine what mediators are responsible for up-regulating these molecules with metastasis.

Other projects involve the identification and characterization of two relatively new collagen types, types XX and XXIV. Collagen XXIV is a new fibrillar collagen expressed in bone and cornea. This collagen appears to be of ancient origin, being closely related to collagens found in invertebrates. Collagen XX is a Fibril-Associated Collagen with Interrupted Triple-helices (FACIT), and may be another fibril diameter regulator.

	Gordon, M.K., Foley, J.E., Hahn, R.A., Zhou, P., Chen, Y., Foley, J.W., Nurminsky, D., and Gerecke, D.R. Regulation of the chicken type XIV collagen gene (Submitted).
	Koch, M., Bhatt, P., Hahn, R.A., Zhou, P., Gerecke, D.R., Burgeson, R.E. and Gordon, M.K. Collagen type XXIII, a novel transmembrane collagen. (Submitted).
	Tzortzaki, E.G., Morio, L., Tischfield, J.A., Sahota, A., Gordon, M.K., and Gerecke, D.R. Expression of FACIT Collagens XII and XIV During Bleomycin-Induced Pulmonary Fibrosis in Mice. Anat. Rec. 275:1073-80, 2003.
	Koch, M., Laub, F., Zhou, P., Hahn, R.A., Tanaka, S., Burgeson, R.E., Gerecke, D.R., Ramirez, F., and Gordon, M.K. Collagen XXIV, a vertebrate fibrillar collagen with structural features of invertebrate collagens: selective expression in developing cornea and bone. J. Biol. Chem. 278:43236-44, 2003.