A major focus in our laboratory is understanding the structure and functions of the cells and the ECM of the cornea. The transparent cornea provides two thirds of the refractive power of the eye and serves as a protective barrier through unique adaptations of the cells and the ECM. The stromal ECM connective tissue is a highly organized array of collagen fibrils and regulatory proteoglycans produced by a specialized fibroblast, the keratocytes. We are trying to understand properties of keratocytes, their development and whether they can be maintained in culture to produce a cornea-like stromal ECM.
Keratoconus is a degenerative thinning and weakening of the corneal ECM, consequent bulging of the cornea with progressive loss of vision. Affecting 1 in 1000 people, it is the second most common reason for cornea transplants worldwide. While the etiology of keratoconus is not fully understood, interactions of genetic factors with environmental stressors are suspected. Our ongoing work on keratoconus is investigating epithelial and keratocyte dysfunctions, and the altered ECMs they produce. The pathogenic cellular and ECM changes in keratoconus are increasingly thought to be due to the accumulation of multiple deleterious genetic variants in an individual. Our collaborative and interdisciplinary team is conducting whole exome and genome sequencing to identify pathogenic genetic variants in familial and isolated keratoconus.
We are interested in the role of small leucine-rich repeat proteoglycans (SLRPs), lumican, biglycan and decorin in cell and tissue functions. As structural proteins of the ECM, these SLRPs interact with collagen fibrils and regulate collagen assembly and connective tissue structure. However, recent studies indicate additional interactions of SLRPs with cell surface receptors that influence cell migration, proliferation and induction of pro-inflammatory cytokines in an ECM that is remodeling during infections and inflammation. Our studies show that mice lacking lumican systemically, when challenged with bacterial infections of the cornea (Shao, 2013), or the lungs (Shao, 2012), are unable to clear the infection, and display more severe disease symptoms. We discovered that lumican released by activated fibroblasts, binds to the surface of neutrophils and promotes neutrophil migration (Lee, 2009). Lumican (Wu, 2007), and the other SLRPs interact with pathogen recognition receptors on macrophages and dendritic cells to modulate host response to infections. We have several projects studying how these SLRPs regulate bacterial and viral infections and autoimmunity.