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1) The pathogenesis of IBMPFD:
Fundamentally two questions are being addressed by our research projects (A) how do IBMPFD mutations in VCP effect its function and (B) how does IBMPFD mutant VCP lead to muscle weakness.
2) Endoplasmic reticulum associated degradation (ERAD) in mature skeletal muscle:
Skeletal muscle has a large endoreticular network that includes the sarcoplasmic reticulum and endoplasmic reticulum. We are interested in defining (A) where does ERAD occur in skeletal muscle and (B) what is the consequence of impaired ERAD in skeletal muscle. 3) Protein inclusions in skeletal muscle: Suprisingly, little is known about how protein aggregates are formed and cleared in a multinucleated syncytium such as mature myofiber. We are interested in (A) identifying the machinery necessary for inclusion formation and (B) how they are degraded in normal and diseased skeletal muscle.
4) Novel functions for VCP:
VCP has many identified functions. By characterizing the phenotype of IBMPFD and other mutations in VCP in cell culture and animals, we propose to identify novel and important roles for VCP in normal and diseased tissue.
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