Shukti Chakravarti Lab

Research area: Extracellular matrix and tissue homeostasis

The Shukti Chakravarti Laboratory is interested in the regulation of cellular functions and tissue homeostasis by the extracellular matrix. The laboratory investigates functions of collagen-associated extracellular matrix proteins and proteoglycans, lumican, fibromodulin and biglycan in maintaining connective tissue architecture and cellular functions. Lumican regulates collagen fibril structure such that gene targeted mice deficient in lumican manifest Ehlers Danlos Syndrome-like skin fragility, tendon weaknesses and corneal opacity. These ECM proteins also regulate host innate immune response, either by interacting with toll-like receptor (TLR) signals to promote sensing of pathogen-associated molecular patterns or presenting as danger signals themselves. Our investigation of the ECM centers on two barrier tissues, the cornea of the eye and the intestinal mucosa and submucosa.

Inflammatory Bowel Disease: Crohn’s disease and ulcerative colitis are two major IBD types. Our works have identified gene expression patterns of these two types of IBD from surgical specimens and endoscopic pinch biopsies. We have developed a mouse model of chronic colitis using trinitrobenzene sulfonic acid, and by microarray gene expression profiling of the mouse colon at the early and late stages of colitis investigated inflammatory and fibrosis-related genes. Using a few different mouse models of IBD and the proteoglycan knockout mice, we are now investigating how the ECM proteoglycans regulate immune cell functions in the intestine.

Corneal infection and inflammation studies: The cornea is an avascular specialized type of barrier tissue that maintains an immune privileged status through an active innate and restricted adaptive immune response. Our goals are to understand how the corneal proteoglycans regulate innate immune response in the context of infections and wound healing. Lumican interacts with CD14, an adaptor protein that conveys bacterial lipopolysaccharides to TLR4 and promotes induction of pro-inflammatory cytokines and phagocytosis of gram-negative bacteria.  We recently identified antimicrobial peptidoglycan recognition proteins in the corneal epithelium Pglyrp1-4; their roles in bacterial infections of the cornea are under investigation as well.

Keratoconus: This is a thinning ectatic disease of the cornea affecting 1 in 2000 in the early teenage. It is progressive, vision-disruptive, ultimately requiring cornea transplantation. Keratoconus is not overtly inflammatory, but it is often linked to atopy and the tear film shows an imbalance in TH1, TH2 and TH17 cytokines. The major structural feature is a weakening and thinning of the corneal stroma with abnormal collagen and proteoglycan distribution and structure. We are investigating the pathophysiology of keratoconus using a few different approaches: 1) quantitative gene expression proteomics of the cornea from surgical buttons, 2) identifying regulatory micro RNA that may explain some of the gene expression and protein changes.3) Cells isolated from the corneal stroma keratoconus samples show expedited cell death in culture and are being explored for use as a cell culture model of the disease.

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