We are interested in the extracellular matrix (ECM) and how it regulates cellular functions and tissue homeostasis. Our pioneering works on an ECM protein/proteoglycan, lumican, established its central role in regulating collagen fibril structure. Mice deficient in lumican harbor ECM collagen defects in the skin, cornea and tendon and show skin and tendon fragility, corneal opacity and thinning. Lumican contains tandem repeats of leucine rich repeat motifs and shares structural similarities with innate immune toll-like receptors (TLR). We hypothesized that in the ECM lumican serves as a pathogen recognition protein. We found that lumican interacts with CD14, a cell surface pathogen recognition adaptor protein, to regulate TLR4 mediated innate immune response to bacterial lipopolysaccharides (LPS). Thus, lumican-deficient mice are hypo-responsive to LPS, and survive better than wild type mice in LPS-sepsis but cannot clear Pseudomonas infections of the eye and lungs. We also found that lumican interacts with cell surface integrins and regulates neutrophil and macrophage migration. Additional studies are underway to understand functions of lumican and other related proteogycans in cellular immune responses and their implications in health and disease.
We are investigating the ECM in inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease. We elucidated signature gene expression patterns for IBD subtypes by microarray-based gene expression profiling of total RNA extracted from endoscopic biopsy tissues. These studies identified distinctive changes in ECM collagens and proteoglycans in the context of inflammation and fibrosis. Using a mouse model of chronic colitis we found that lumican modulates early inflammation and lumican deficient mice show aggravated colonic tissue damage. We are now beginning to address how lumican and other related proteoglycans modulate immune cell functions in inflammation and infections.
Another project in our lab focuses on Keratoconus, an ECM-centric corneal disease that affects ~1 in 1000 individuals worldwide. The stromal connective tissue progressively becomes weak and thin, causing high astigmatism, scarring, and vision loss in cases with severe keratoconus. As there are no ideal animal models for keratoconus, we have developed a cell culture disease model to investigate underlying causes of why the stromal cells are unable to establish or maintain a healthy collagenous ECM. We are using whole genome and exome sequencing and functional studies using stromal cell cultures to identify genes and signaling pathways that cause keratoconus, to ultimately develop potential targets for therapeutic interventions.