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UI's Campbell continues to identify molecule's many roles

IOWA CITY, Iowa -- A University of Iowa researcher and members of his laboratory have learned more about a molecule that may play an important role in human development and the formation of many diseases, including muscular dystrophy, according to articles appearing in today's issues of Cell and Science.

In his latest research, Kevin P. Campbell, Ph.D., Howard Hughes Medical Institute investigator and UI professor of physiology and biophysics, and neurology, has shown that the body requires the cell surface receptor dystroglycan to develop basement membranes. In separate but related work, Campbell, in collaboration with researchers in other parts of the country, also has found that a protein subunit of dystroglycan is a receptor for some viruses that cause fatal hemorrhagic fever and for Mycobacterium leprae (M. leprae), the bacteria that causes leprosy.

"Our understanding of dystroglycan has increased dramatically over the past two years," Campbell said. "Through structural studies, analysis of its binding partners and targeted gene disruptions, we know dystroglycan plays a role in several muscular dystrophies, serves as a receptor for a human pathogen and is involved in early development. This insight could have implications for treating various conditions in the future."

Campbell's Cell article, co-authored with UI post-doctoral research fellow Michael Henry, Ph.D., showed that dystroglycan affects basement membrane development by interacting with the extracellular matrix protein laminin. A basement membrane is a structurally distinct, extracellar layer closely applied to the bottom surface of epithelia, muscle cells, fat cells and Schwann cells (cells that envelope and protect peripheral nerve fibers). A basement membrane serves as a selective filter and has other structural and development functions. In earlier work, Campbell's lab, in collaboration with Dr. Roger Williamson, UI professor of obstetrics and gynecology, showed that mice lacking dystroglycan exhibited perturbed basement membranes and died after only a few days of embryonic development.

"Our study of dystroglycan's role in the formation of the basement membrane helps us to better understand the basic science of dystroglycan," Campbell said. "Dystroglycan is essential for a number of different functions, including the development of muscular dystrophy. It doesn't cause muscular dystrophy, but it is intimately involved in the muscular dystrophy process. Our current work is giving us a clue as to where to look for the pathogenesis of muscular dystrophy."

For more than a decade, Campbell has been looking into the causes and possible cures for the various forms of muscular dystrophy. Dystroglycan is a component of the dystrophin-glycoprotein complex, which Campbell originally identified. Problems with this complex result in forms of muscular dystrophy.

Muscle is not the only type of cell that dystroglycan affects. It is widely expressed in many cell types. The two Science articles examine a subunit of dystroglycan and its role in the cause of leprosy and hemorrhagic fever.

In the Schwann cells covering peripheral nerves, the subunit serves as a receptor for the pathogenic bacteria that causes leprosy. Once attached, the bacteria M. leprae invades the Schwann cells and causes significant damage to peripheral nerves, leaving patients with disabilities and deformities. Although antibiotic therapy can effectively cure leprosy, it cannot reverse the patients' nerve function loss.

"Understanding how the subunit of dystroglycan affects the leprosy-causing bacteria may eventually lead to developing a new therapy to block the uptake of the bacteria into the peripheral nerves and thus prevent nerve damage," Campbell said.

The same subunit of dystroglycan also serves as a receptor for viruses, such as the ones that cause hemorrhagic fever. Campbell, members of his lab and researchers from the Scripps Research Institute looked at two particular types of hemorrhagic fevers: Lymphocytic Choriomeningitis Virus (LCMV) and Lassa Fever Virus (LFV). The scientists found that the subunit serves as a cellular receptor for both LCMV and LFV. Hemorrhagic fever can be fatal. Annually, there are about 250,000 cases of LFV and more than 5,000 deaths.

Campbell and others in his lab will continue to look at the many roles of dystroglycan. Campbell wants to figure out the structure-function relationship of the molecule with respect to assembly of the basement membrane and identifying important sites for viral and bacterial reception.