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What the Gut and the Eye Have in Common
Date: January 1, 2013
Cell biologist Shukti Chakravarti may have come to Johns Hopkins because of her husband, but her research talents speak for themselves.
Chakravarti moved to Hopkins from Case Western in 2000 when her husband, Aravinda, was recruited to head the McKusick-Nathans Institute of Genetic Medicine. At the time, she had developed a research niche in connective tissue proteins, and former Medicine Director Edward Benz made her an offer to expand her work on connective tissue-related problems in inflammatory bowel disease (IBD).
Chakravarti, who was promoted to professor in fall 2012, has made a name for herself studying connective tissue proteins of the extracellular matrix (ECM)—noncellular material comprising most of the cornea, cartilage and lining of the gut. She has almost single-handedly defined the role of a protein called lumican, which in one form associates with collagens and in another sits on inflammatory cells, neutrophils and macrophages, helping them recognize bacterial pathogens. class="Apple-tab-span"
In the eye, Chakravarti’s work has shown how lumican engineers the cornea’s transparency by directing the way collagen molecules orient themselves, while during infections it modulates inflammatory responses. She is designing lumican variants to test their therapeutic potential in mouse models of the corneal inflammation keratitis. Her lab also has been investigating a progressive corneal disease called keratoconus, conducting proteomics studies and analyses of cytokine levels in patients’ tear samples. Her theory is that the altered cytokine and protease balance underlying chronic mild inflammation degrades the corneal ECM. She plans to develop cell culture and mouse models to further investigate disease progression, biochemical pathways and therapeutic interventions.
In the gut, Chakravarti has focused on how the ECM modulates immune response and inflammation in IBD, Crohn’s disease and ulcerative colitis—conditions with variable, overlapping clinical features and pathophysiologies. Her lab obtained global gene expression patterns from surgical specimens of the colon and published one of the earliest studies identifying a panel of genes showing distinctive gene expression differences between Crohn’s and ulcerative colitis.
Her lab also developed a mouse model of chronic colitis by introducing a low-dose irritant into the animals’ colons. To discover lumican’s role, Chakravarti and colleagues used the intestinal irritant on knockout mice manipulated to not make lumican. They found that in early-stage colitis, inflammation doesn’t develop properly without lumican, which makes the damage worse. Short-term inflammation that allows recovery was muted without lumican. Knockout mice also had a harder time gaining lost body weight, a hallmark of IBD.
“We think lumican adds another layer of control by modifying inflammatory response,” Chakravarti says. “And its relatives do similar things.”
Studying such different areas of the body isn’t as unusual as one might think, Chakravarti says. Because she’s working at the cellular level, studying how cells cause inflammation or migrate to the site of injury, “it’s so fundamental, I can go from one tissue to another looking at cell-ECM interactions.”
She’s also used her talents to co-chair the department’s research retreat for the past two years, attracting speakers like Nobel prize-winning scientist Harold Varmus, director of the National Cancer Institute, and driving more participation from young investigators, trainees and fellows.
Gastroenterologist Steven Brant, who has collaborated with Chakravarti on IBD research, says, “she has done extensive work on lumican and developed a lot of the field herself, which for anyone is remarkable.
“She’s a solid investigator. We could use a thousand more scientists just like her.”