Research | Higgins Lab
Projects
Basic Research Projects
Mechanisms of Intestinal Fibrosis
This project, sponsored by the NIH, is designed to better understand why people with Crohn's develop intestinal scarring. We started with strictures from patients with Crohn's disease who had surgery, and found that the pieces of intestine that were removed were quite stiff. These samples had large amounts of collagen and extracellular matrix, that had extensive crosslinking making it more stiff.
We evaluated myofibroblast cells from human intestines and showed that they become more fibrogenic (scar-generating) when grown on a stiff matrix. The stiff matrix itself causes a change to a more fibrogenic state in these cells, suggesting that this could be a mechanism for propagating and increasing scar tissue once a stricture is started.
We are evaluating the effects of the matrix structure on the formation of strictures in cell culture models and in rat and mouse models of intestinal scarring. We hope to develop ways to identify early scarring with ultrasound elastography, and test whether physical changes (balloon dilation), chemical reactions (breaking crosslinks or digesting collagen), or anti-fibrotic medications can slow the progress of fibrosis or even reverse intestinal scarring (fibrosis).
Research Needs
We are hoping to obtain funding for experiments to find out how intestinal scarring starts and what makes it continue, despite current medical therapies.
We are hoping to obtain funding for experiments to test new therapies designed to reverse scarring in skin and lung diseases in models of intestinal fibrosis. Currently, surgery or balloon dilation through an endoscope are the only treatment options for intestinal scarring.
Clinical Research Projects
Research Needs
We are hoping to obtain funding for development of preliminary data on the bacteria that line the intestine and affect the recurrence of inflammation in IBD. This is clearly important in the recurrence of Crohn's disease after surgery, and in pouchitis, two conditions that respond to antibiotic treatment. We are particularly interested in how changes in the microbes, and antibiotic effects, can reduce recurrence of flares.
We are hoping to obtain funding for development of prototypes of drug-eluting setons with our colleagues in biomedical engineering. Current therapies slow down fistula formation, but do not completely heal fistulas. We would like to combine setons with modern drug-eluting technology to stimulate healing.
We are hoping to obtain funding for studies of stool and blood biomarkers of future flares. Currently, we are not very good at predicting who will flare, and who needs adjustment in their medications to prevent a flare before it occurs. Biomarkers appear to have some promise for adjusting therapy before flares occur.
We are hoping to obtain funding for studies of blood biomarkers of ongoing intestinal scarring. Currently, we are not very good at predicting who will develop intestinal scarring and blockages, and who needs adjustment in their medications to prevent scarring before it occurs. We have an agreement with Pfizer to investigate this promising area, but we need funding for the clinical sample collection.
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Lori Hirshman
