Skeletal muscle development, or myogenesis, represents an ideal model system for studying cellular processes such as cell migration, cell
signaling, cell cycle regulation and cell differentiation. Understanding myogenesis is extremely important, since myoD -/-, myf5 -/- deficient
mice which lack normal muscle development die at birth, and mutant mice lacking muscle specific stem cells (or satellite cells) cannot
regenerate muscle in response to injury. The objective of my current research program is to elucidate the cell signaling and epigenetic
mechanisms which commit muscle precursor cell to specific myogenic lineages and the role of specific myogenic lineages in the development and
regeneration of different muscle fibre types. Specifically, I am using several different rodent models (ex. normal and GFP-expressing nude rats,
normal and Pax 7 -/- KO mice) to explore six major themes, including:
1) the epigenetic mechanisms involved with myogenic lineage specification
2) the role of embryonic signaling molecules (such as Shh, Wnts and BMPs) in programming muscle precursor cells into either fast or slow myogenic lineages
3) the ability of over-expression of fibre type specific genes (such as calcineurin, Sox6 and Six1/eyal) to dictate the fibre type of muscle satellite cells
4) the importance of p38 signaling in determining myogenic lineage specification
5) the ability of slow fibres derived from embryonic myoblasts to remodel to fast fibres in response to thyroid hormone and
6) the ability of slow-lineage specified muscle satellite cells, engineered to constitutively express Connexin 43 (Cx43), to become functionally integrated in vivo following direct injection into adult rat myocardium.
The experimental approaches used to pursue these objectives will include cell culture/transduction, cell injection/immunolocalization, immunoprecipitation/western blot analysis, RT/real time PCR and microarray analysis. Discovering the molecular basis for these signaling and epigenetic mechanisms will improve our understanding of how normal and diseased muscle adapt, regenerate and age.
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