The cornea is a specialized protective barrier providing 70% of the refractive power of the eye. It is rich in extracellular matrix ECM) proteins that provide structural support, a stem cell niche, innate immune protection and limit adaptive immune response to restrict inflammation, fight infections and allow unhampered vision. Our research focuses on extracellular matrix proteins that regulate collagen fibril structure and corneal transparency, interact with cell surface receptors and modulate inflammatory cell influx. Mice deficient in lumican, one such extracellular matrix protein, develop corneal opacities and respond poorly to injuries, providing the first mouse model for corneal dystrophies. Lumican also aids host recognition of bacterial antigen through its interactions with the toll-like receptor 4 complex and promotes neutrophil migration by binding to surface integrins. These findings are being further investigated. We have recently discovered a secreted antibacterial protein on the surface of the corneal epithelium. We are investigating the expression and routing of this protein in response to bacterial exposure and its antibacterial properties in mouse models of corneal infections.

Keratoconus is a progressive disease where the cornea is abnormally thin and steep. Abnormal corneal ECM or increased degradation of the corneal ECM due to altered cytokine and protease balance underlying chronic mild inflammation may be factors in this disease. We are investigating these possibilities using proteomic approaches and analyses of cytokine levels in tear samples of patients. http://www.jhu.edu/schakravarti/kcn/index.html. Future studies will include mouse models to investigate disease progression, biochemical pathways and therapeutic interventions.

A second research area in our laboratory centers on modulation of innate immune response and inflammation by the extracellular matrix in inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. To begin understanding these complex diseases we obtained global gene expression patterns from surgical colonic specimens initially and subsequently from endoscopic pinch biopsies. We also developed a mouse model of chronic inflammation and fibrosis to elucidate pathologic changes in extracellular matrix proteins.

Select Publications

1. Lawrance IC, Fiocchi C, Chakravarti S. 2001. Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes.Hum Mol Genet.10:445 PMID:11181568.

2: Wu F, Vij N, Roberts L, Lopez-Briones S, Joyce S, Chakravarti S. 2007a. A novel role of the lumican core protein in bacterial lipopolysaccharide-induced innate immune response. J Biol Chem. 282:26409.  PMID:17616530.

3: Wu F, Dassopoulos T, Cope L, Maitra A, Brant SR, Harris ML, Bayless TM, Parmigiani G, Chakravarti S. 2007b.  Genome-wide gene expression differences in Crohn's disease and ulcerative colitis from endoscopic pinch biopsies: insights into distinctive pathogenesis. Inflamm Bowel Dis.807:21. PMID: 17262812.

4. Wu, F. and Chakravarti, S. 2007c Differential Expression of Inflammatory and Fibrogenic Genes and Their Regulation by NF-{kappa}B Inhibition in a Mouse Model of Chronic Colitis. J Immunol.179: 6988

5: Wu F, Lee S, Schumacher M, Jun A, Chakravarti S. 2008 Differential gene expression patterns of the developing and adult mouse cornea compared to the lens and tendon. Exp Eye Res.87:214-25 PMID:18582462.