Grant: Operating Grant

The Nuclear Factor kappaB (NF-kappaB) signaling pathway is a complex signaling module that is critical for normal skeletal muscle function, such as promoting recovery in response to muscle injury. However, there is strong evidence that NF-kappaB signaling is also involved in the pathology associated with various muscle diseases, such as Duchenne's muscular dystrophy (DMD), inflammatory myopathies, and skeletal muscle atrophy. As such, NF-kappaB has become an attractive drug target for the treatment of muscle disease. We have recently found that the cellular inhibitors of apoptosis, cIAP1 and cIAP2 (genes cloned in our laboratory and shown to be involved in the regulation of cell death) are required for various aspects of NF-kappaB signaling in skeletal muscle. This discovery has raised the exciting possibility that cIAP1/2 may be a potential therapeutic targets for various muscle diseases that rely on NF-kappaB signaling. We propose to elucidate the role and mechanism of action cIAP1/2 in NF-kappaB signaling in skeletal muscle, and evaluate its contribution to the pathology of muscular dystrophy and skeletal muscle atrophy. Moreover, as we have in hand several drugs and reagents that potently and specifically target both cIAP1 and cIAP2 for destruction, we will evaluate the therapeutic potential of these reagents in the treatment of muscle disease.