The Shukti Chakravarti Laboratory is interested in the regulation of cellular functions and tissue homeostasis by the extracellular matrix (ECM). 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 responses 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 Diseases (IBD): 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. [Chakravarti3.jpg]

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 corneal proteoglycans regulate innate and adaptive immune responses in the context of infections and wound healing. Lumican interacts with CD14 that conveys bacterial lipopolysaccharides to TLR4 and promotes induction of pro-inflammatory cytokines and phagocytosis of gram-negative bacteria.
We are also investigating the role of four antimicrobial peptidoglycan recognition proteins in corneal host defense.

Keratoconus: This is a thinning ectatic disease of the cornea that affects 1 in 2000 individuals within their first two decades of life. It is progressive, vision-disruptive, and without a cure, it is the leading cause for cornea transplantation. Keratoconus is a complex disease that is regulated by multiple genes and environmental factors. We are investigating keratoconus pathophysiology using multiple approaches. Contributions of specific genes are being sought by a) exome sequencing of DNA from patient blood, b) differential transcriptome and proteome of corneal tissues. We have established primary cells from keratoconus corneas to examine features of the disease in culture.  

Select Publications

1. Chakravarti S, Magnuson T, Lass JH, LaMantia C, Jepsen KJ, Carroll H. Collagen fibril defects affecting skin and cornea in lumican-deficient mice. J Cell Biol. 1277-1286. PubMed PMID: 9606218;PubMed Central PMCID: PMC2137175.

2. Lawrance IC, Fiocchi C, Chakravarti S. 2001. Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes.Hum Mol Genet.10:445 PMID:11181568.

3. Lawrance IC, Wu F, Leite AZA, Willis J,West GA, Fiocchi C, Chakravarti S. A murine model of chronic inflammation-induced intestinal fibrosis down regulated by antisense NF-κB. Gastroenterology. 2003; 125: 1750-1761. PubMed PMID: 14724828.

4: Wu F, Vij N, Roberts L, Lopez-Briones S, Joyce S, Chakravarti S. 2007a. A novel role of the lumican core protein in bacterial lipopolysaccharide-induced innate immune response. J Biol Chem. 282:26409.  PMID:17616530.

5. Wu, F. and Chakravarti, S. 2007b.  Differential Expression of Inflammatory and Fibrogenic Genes and Their Regulation by NF-{kappa}B Inhibition in a Mouse Model of Chronic Colitis. J Immunol.179: 6988.

6. Lee, S., Bowrin, K., Hamad, A. and Chakravarti, S. 2009a Extracellular matrix lumican deposited on the surface of neutrophils promotes migration by binding to 2 integrin. J. Biol. Chem. 284:23662-9.PMID: 19531489.

7. Ghosh A, Lee S, Dziarski R, Chakravarti S. 2009b A novel antimicrobial peptidoglycan recognition protein in the cornea. Invest Ophthalmol Vis Sci. 2009 Apr 22. [Epub ahead of print] PubMed PMID: 19387073.

8. Lohr, K, Sardana, H, Lee, S, Wu, F, Huso, DL, Hamad, AR, Chakravarti, S. Extracellular matrix protein lumican regulates inflammation in a mouse model of colitis. Inflamm Bowel Diseases, 2011 Apr 11. doi: 10.1002/ibd.21713. [Epub ahead of print]. PMID: 21484968; PubMed Central PMCID: 3135758.

9. Scott S-G, Jun AS and Chakravarti S. Sphere formation from corneal keratocytes and phenotype specific markers. Experimental Eye Research, 2011 Dec;93(6):898-905. Epub 2011 Oct 21. PMID: 22032988 PMCID: 3225580.

10. Shao H, Lee S, Gae-Scott S, Nakata C, Chen S, Hamad AR, Chakravarti S. Extracellular matrix lumican promotes bacterial phagocytosis and Lum-/- mice show increased Pseudomonas aeruginosa lung infection severity. J Biol Chem. 2012 Aug 3. [Epub ahead of print] PubMed PMID: 22865855  PMCID: 3476255.

11. Shao H, Scott SG, Nakata C, Hamad AR, Chakravarti S. Extracellular matrix protein lumican promotes clearance and resolution of Pseudomonas aeruginosa keratitis in a mouse model. PLoS One. 2013;8(1):e54765. doi: 10.1371/journal.pone.0054765. Epub 2013 Jan 24. PubMed PMID: 23358433; PubMed Central PMCID: PMC3554612.