Inside Pediatrics Spring 2023

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 (TGF β 1), clinical studies using drugs to inhibit TGF β 1 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 TGF β . While it’s been known for some time that the Smad2 and Smad3 factors are important players in the TGF β pathway, Lopez’s research identified 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 2022. “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.”

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