Investigator: Rajanikanth Vangipurapu PhD
Category: Research - Basic
Misexpression of the DUX4 gene in skeletal muscle of FSHD patients is responsible for muscle degeneration associated with the disease. We have recently discovered that p38 kinase inhibitors potently suppress expression of DUX4. The first drug intended to suppress DUX4 expression (p38 inhibitor losmapimod) is now entering clinical trials in FSHD patients while we still know very little about how p38 inhibition results in suppression of DUX4. The main mechanism linking mutations in FSHD with misexpression of DUX4 is epigenetic de-repression, or opening of the normally closed chromatin region around the DUX4 gene. There is little information about the subsequent steps that are required to produce the myotoxic DUX4 protein including cell signaling cascades and transcription factors that lead to synthesis of DUX4 mRNA. We have identified a class of transcription factors that are important for DUX4 expression, are known to be regulated by p38 and may link the expression of DUX4 to the p38 signaling cascade. We propose to identify the specific family member, determine where it binds to regulate the DUX4 gene and investigate how its activity is regulated by p38 kinase.