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.
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Keratoconus (1 in 2000), is a degenerative thinning of the cornea that affects people in the teenage years and progresses over 4-5 decades. It leads to the loss of vision and 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 to cause keratoconus. We hypothesize that the degenerative changes in the corneal ECM in keratoconus are due to pathogenic changes in the epithelium and keratocytes, and the altered ECMs they produce which in turn affect cellular functions. We further propose that these pathogenic changes are due to the accumulation of multiple individual deleterious genetic variants.
We study an ECM proteoglycan family called the small leucine repeat-rich proteoglycans (SLRPs). Our studies led to a paradigm shift in understanding the functioning of SLRPs. Initially believed to be only structural proteins, we have demonstrated that SLRPs are also cell signaling proteins of the ECM. Levels of many SLRPs, including a specific SLRP called lumican, increase in infections and inflammation of the cornea, lungs, skin and the gut in humans. As structural proteins SLRPs interact with collagen fibrils and regulate collagen assembly and connective structure. However, newly synthesized SLRPs, or those released from a remodeling ECM during infections and inflammation, can interact with cell surface receptors to regulate immune cell functions.
Keratoconus is a degenerative thinning of the ECM of the cornea. The cornea is a specialized ECM-rich protective barrier tissue of the eye made up of collagens, glycoproteins, and proteoglycans, like lumican, keratocan, biglycan and decorin. In keratoconus the corneal ECM deteriorates, becomes thin and protrudes. Patients suffer from high astigmatism, scarring and progressive loss of vision. Keratoconus is managed by contact lens use and UV cross-linking of collagens (CXL) to temporarily strengthen the ECM connective tissue at the early stages. In advanced stages cornea-transplants are required, making keratoconus a leading cause for cornea-transplants worldwide. Although influenced by multiple environmental stressors, keratoconus has a strong genetic basis where multiple genetic variants individually or in combination are hypothesized to be causal.
Pioneering work in our laboratory has identified and characterized a group of small leucine-rich repeat proteoglycans (SLRP) of the ECM. Proteoglycans are glycoproteins post-translationally modified with glycosaminoglycan side chains. We focused on a prototype SLRP, lumican. It is a keratan sulfate proteoglycan in the cornea where it regulates collagen fibril structure and corneal transparency. The glycoprotein form of lumican is widely present in many tissues where it has other immunoregulatory functions. Our prior work on inflammatory bowel disease, corneal and lung infections show that lumican is induced under inflammatory conditions, and that it interacts with β2 integrin to promote neutrophil and macrophage chemotaxis. Recently, we found that lumican interacts with CD14 on the surface of macrophages to regulate toll-like receptor (TLR) 4 response to bacterial lipopolysaccharides (LPS).