Spring 2010
Faculty Focus

synapse: University of Nevada, Reno School of Medicine

Dean Burkin, Ph.D.

Dean Burkin, Ph.D., earned a five-year, $1 million National Institutes of Health grant to study integrin-based therapies for muscular dystrophy. Photo by Laura Levin

The glue that binds

Story by Laura Levin

Dean Burkin, Ph.D., associate professor of pharmacology at the School of Medicine, discovered a potential therapy for the most common form of muscular dystrophy.

"Duchenne Muscular Dystrophy is an X-linked disease (on the X-chromosome) that affects one of 3,500 newborn boys," said Burkin, who also serves as the director of the Nevada Transgenic Center.

"Around 45,000 children suffer from this disease in the United States and European Union."

Children with this genetic disease are diagnosed by five years of age. Many are confined to a wheelchair by their early teens and die in their 20s or 30s from cardiopulmonary failure. There is no effective treatment or cure for this disease, which is caused by mutations in a gene encoding a critical muscle protein called dystrophin.

"Dystrophin is a molecular glue that links the inside of the cell to the extracellular matrix on the outside of the cell," explained Burkin.

"The lack of this glue causes muscle fibers to pull away from each other with progressive use. In these patients, it eventually leads to severe muscle damage."

Muscle cells also have "back-up glue" called alpha7beta1 integrin, which also mediates muscle cell attachment to the extracellular matrix.

Using transgenic mouse technology, Burkin and his colleagues showed increased alpha7beta1 integrin alleviates muscle disease in dystrophic mice.

Researchers at the medical school found a naturally occurring protein in the human body, called laminin-111, that binds to both alpha7beta1 integrin and dystrophin. Treating muscle cells with laminin-111 increased the levels of alpha7beta1 integrin.

Laminin-111 is a major component of the muscle extracellular matrix and is produced during muscle development and in adult kidneys. "Because adults don't produce laminin-111 in their muscles, it can easily be tracked," Burkin said. "And because it occurs naturally in our kidneys, our bodies won’t reject it."

Burkin’s lab tested laminin-111 in mice with muscular dystrophy and found exercise caused muscle damage in the untreated mice, but not in the treated animals.

"This was a significant finding suggesting that laminin-111 was really acting protectively in the muscle to prevent degeneration," said Burkin.

The researchers also tracked the protein and were surprised to find it reached all major muscle groups in mice, including the heart and the diaphragm, which are most severely affected in Duchenne patients. Results from these studies were recently published in Proceedings of the National Academy of Science.

"Essentially, laminin-111 reloads the extracellular matrix increasing the levels of the integrin bonding glue and prevents further damage," Burkin said. "This could be developed into a drug for the patients, if the work in the mouse models that we’ve been using translates to human studies."

The University of Nevada, Reno recently aligned with Prothelia, Inc. a biopharmaceutical company, to begin making a human version of the laminin-111 for possible clinical trials.

"The next step is to find out how effective laminin is after disease onset. We are currently investigating if laminin-111 protein therapy can reverse the disease’s progress or at least stop it in its tracks after it has already progressed," Burkin said.

Burkin, a New Zealand native, received undergraduate degrees in biology and developmental biology from Victoria University of Wellington, New Zealand.

He completed his doctorate in biochemistry and genetics at the University of Colorado Health Sciences Center and postdoctoral training at Cambridge University, England. He then joined the University of Illinois to complete postdoctoral research before coming to the School of Medicine in 2003.