Dr. Michael Lopez received a nearly $1 million grant to study a new pathway in Duchenne muscular dystrophy.
What happens when you knock out a ubiquitous protein in muscle that appears to be involved in numerous neuromuscular diseases, including Duchenne muscular dystrophy (DMD)? That’s the question Children’s of Alabama pediatric neurologist Michael Lopez, M.D., Ph.D., and his mentors, University of Alabama at Birmingham (UAB) professor Peter King, M.D., and assistant professor Matthew Alexander, Ph.D., are trying to answer.
Lopez recently received a Career Development Award worth nearly $1 million from the National Institute of Neurologic Disorders and Stroke to better understand a novel pathway involved in the development and progression of DMD.
The disease, which primarily affects males, is caused by a mutation in the gene that encodes for the dystrophin protein, which is critical for musculoskeletal health. Without this protein, muscles degrade over time, resulting in a severe paralysis that affects breathing and eventually causes the heart to fail. Patients typically die in their early 20s or 30s.
There is no satisfactory treatment for DMD. A multidisciplinary approach involving neurology, cardiology, pulmonary care and rehabilitation—among other specialties—helps patients manage the disease. Immune-dampening corticosteroids are the primary medical therapy.
Lopez and his team identified a new pathway involved in the sustained inflammation that underlies the disease. While chronic inflammation is driven, in part, by elevated levels of the cytokine transforming growth factor β (TGFβ1), clinical studies using drugs to inhibit TGFβ1 have been, by and large, unsuccessful. Lopez thinks that’s because the TGF signaling is more complicated, so any attempt to reduce levels must account for downstream signaling via transcription factors, called Smads, that receive instructions from TGFβ.
While it’s been known for some time that the Smad2 and Smad3 factors are important players in the TGFβ pathway, Lopez’s research identified another Smad called Smad8 that is not only turned on in a cellular model of DMD but is 48 times higher than other Smad factors. His findings were published in the International Journal of Molecular Science in July. “It appears to be a previously unrecognized pathway that could cause larger dysregulation of gene expression within the muscle,” he said.
When the researchers silenced Smad8 in cultured muscle cells, they found the cells differentiated into muscle fibers more successfully. “That’s a key experiment because it shows that too much of Smad8 was likely doing the opposite: preventing the muscle cells from differentiating into myofibers,” Lopez said.
The grant provides the funds to breed transgenic mouse lines in which the gene that encodes for Smad8 is deleted in cells destined to become muscle cells. “That way, we can answer the question, ‘Is it necessary for the normal function of muscle, and does it make DMD less severe in the mouse?’” Lopez said. “The premise is that we can intervene on this pathway and reverse these impairments.”