The specification and differentiation of myoblasts by the action of myogenic transcription factors is a key event in the formation of the skeletal musculature. Following embryonic muscle development, the specification and differentiation of myoblasts remains essential for the maintenance and regeneration of healthy adult muscle in mammals. Failure to maintain muscle homeostasis properly through the establishment of new populations of myoblasts leads to progressive degenerative muscle wasting. However, despite the primary importance of myoblast specification and differentiation for myogenesis, the identities of new molecular players in this process remain unknown. Preliminary studies in the fruit fly, Drosophila melanogaster, have recently identified a novel participant in myogenesis, the conserved nuclear protein Akirin. Akirin appears to play an important yet still unidentified role i the regulation of gene expression during myoblast specification. The overall goal of this proposal is to use Drosophila to identify and characterize the molecular mechanism of gene regulation by Akirin during myogenesis. The rationale for the proposed research is that through understanding the modes of action of novel regulators of myogenesis such as Akirin, the efficacy of therapies aimed at mitigating or reversing muscle wasting can be improved. We will study Akirin's mode of action through two specific aims. First, we will perform deletion analysis to identify the domains of interaction between Akirin and the transcriptional machinery that are critical for Akirin-mediated gene regulation. Second, we will use a double heterozygote assay to identify candidate proteins that interact with Akirin during muscle development, and are essential cofactors for Akirin-mediated gene regulation. Critically, in keeping with the goals of the AREA award mechanism, this project will give undergraduate researchers hands-on experience in a wide variety of molecular, genetic and biochemical techniques, which will provide a valuable skill set for a future career in biomedical research.
Muscle wasting is a common condition in disease states such as neurodegenerative disorders and in patients with advanced forms of cancer. Muscle is formed and maintained by a process called myogenesis, which relies upon a carefully coordinated program of gene expression to ultimately build new muscle and repair damaged muscle. The overall goal of this project is to understand how a novel regulator of myogenesis, Akirin, functions to promote myogenic gene expression;by understanding Akirin function, we can better promote the formation of healthy muscle precursors and improve existing therapies aimed at ameliorating or preventing muscle wasting.
|Salerno, John C; Ngwa, Verra M; Nowak, Scott J et al. (2016) Novel cell-penetrating peptide-adaptors effect intracellular delivery and endosomal escape of protein cargos. J Cell Sci 129:893-7|