Entries by awp-admin

Pathogenesis and genetic causes of keratoconus

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.

Extracellular matrix interactions with immune cells and regulations of host response to infections and inflammation

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.

Keratoconus Study

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.

Immuno-regulatory functions of the ECM

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).