Researchers at Penn State College of Medicine, working with biochemists, geneticists and clinicians at the University of Bern, Switzerland and in the United Kingdom, have discovered an enzyme that has a key role in inflammatory bowel disease (IBD).
The team, co-led by Judith Bond, Ph.D., Distinguished Professor and Chair of Biochemistry and Molecular Biology at Penn State College of Medicine, and Daniel Lottaz, Department of Rheumatology and Clinical Immunology at the University of Bern, Switzerland, could potentially lead to therapies to help the half-a-million Americans affected by ulcerative colitis and Crohn's disease, collectively referred to as IBD.
The enzyme, coded for by the MEP1A gene, is a zinc-containing metalloprotease called meprin, and is abundant in the intestine. A protease is an enzyme that breaks down proteins in the body.
Researchers at Penn State College of Medicine studied the role of meprin in IBD using genetically altered mice lacking the ability to produce the enzyme in collaboration with colleagues in Switzerland who studied the enzyme in IBD patients. Meprin is abundant in the latter part of the small intestine, or terminal ileum, and is also present in the large intestine at a lower level. The European researchers found an alteration in the meprin gene that correlated with IBD. They then compared the levels of meprin in affected and unaffected sections of colons from IBD patients and from healthy people. The amount of enzyme in the IBD patient's inflamed colon was significantly lower than that in normal colon sections. The researchers concluded that their findings strongly correlate the severity of inflammation associated with both Crohn's disease and ulcerative colitis with low meprin levels.
"This discovery is a major advance in understanding the genetic control of inflammation, and of ulcerative colitis and Crohn's disease in particular," Bond said. She discovered meprin more than 25 years ago while at the Medical College of Virginia Commonwealth University. Since then, she has studied the structure and activities of the meprins and has located the genes for the subunits in both the mouse and human chromosomes. After coming to Penn State Hershey in 1992, her studies have focused on the biomedical significance of the meprin proteases. With colleagues from the National Institutes of Health, she found a linkage between the meprin gene and vulnerability to diabetic nephropathy in Pima Indians in the southwestern United States.
"These types of transitional research that provide sound basic understanding of a disease process, coupled with detailed examination and critical interpretation of clinical findings, are dependent upon sustained collaborations based upon trust and respect," Bond said. Before this international effort, she teamed up with kidney specialists at Albert Einstein College of Medicine in New York and with W. Brian Reeves, M.D., at Penn State Hershey to demonstrate that meprin influences the outcome of acute renal failure in mice.