October 28,2022 Our manuscript “Single cell RNA-seq of human cornea organoids identifies cell fates of a developing immature cornea” by Maiti, George and others is now in press in PNAS Nexcus.
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August 26, 2022 Mackenzie Charter is going to graduate school this Fall. While we will miss her, we are proud of her. Good luck with your studies!
August 22, 2022 Hailey Martinez just joined the group to help with our Keratoconus research. Welcome Hailey!
August 1, 2022 Madison Glowacki just joined the group to help with our research on extracellular matrix and immune regulations. Welcome Madison!
June 13, 2022 Sean Ashworth, PhD from the School of Optometry and Vision Sciences, Cardiff University is joining the lab in September this year. Welcome Sean!
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.
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).