Research Overview

We study the role of the extracellular matrix of the cornea in health and disease.

  • Extracellular matrix functions in the healthy cornea
  • Extracellular matrix changes and underlying genetic causes in a degenerative corneal disease called keratoconus
  • Extracellular matrix interactions with immune cells and regulations of host response to infections and inflammation

We are interested in understanding how the extracellular matrix (ECM) regulates cellular functions and tissue homeostasis. The ECM is a network of collagens, proteoglycans, and glycoproteins that facilitates cell communication and function in multicellular organisms. The macromolecular composition and the structure of the ECM change with the needs of the particular tissue. Importantly, in an ECM that is remodeling by degradation and de novo synthesis of proteins, the components are more readily available to interact with cells to provide instructive signals during repair and regeneration. We strive to understand dysregulations in these cell-ECM interactions that form the basis of many pathological conditions.

Extracellular Matrix

Extracellular matrix in the healthy cornea

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.

karatoconus

Extracellular matrix changes and underlying genetic causes in keratoconus

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.

infection and inflammation

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

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.