This proposal is a continuation of a 19-year grant that has been central to my laboratory's studies of muscle development. The focus for the next grant period is an in-depth analysis of a recent, exciting finding by us and others that bone marrow derived cells (BMDC) could provide a reservoir of potential """"""""stem cells"""""""" for myogenesis. Transplantation of green fluorescent protein (GFP) labeled bone marrow into irradiated wild-type donor mice allows the BMDC to be readily tracked.
Specific Aim 1 will determine the basis for the 1,000- fold higher rate of incorporation of BMDC into the paniculus carnosus (PC) relative to other skeletal muscles. The range in frequencies in BMDC incorporation into diverse skeletal muscles (0.01 to 10%) suggests that this phenomenon is not sporadic, but due to properties specific to the PC. Moreover, the extraordinarily robust contribution of BMDC to the PC provides an invaluable assay to identify specific BMDC capable of the transition from bone marrow to muscle, factors that enhance mobilization from marrow, the role of damage in incorporation, and factors that may increase """"""""homing"""""""" to skeletal muscles.
Specific Aim 2 will determine whether BMDC contribute directly to muscle fibers or first become tissue-specific muscle precursors, known as satellite cells, which have well-characterized morphology and patterns of gene expression. The need for stress or damage in these transitions will be investigated. Experiments will determine whether the pathway can be dissociated such that bone marrow cells respond to one set of signals by giving rise to satellite cells and then to a second set of signals that now cause the new donor-derived GFP+ satellite cells to contribute to muscle fibers. If satellite cells that derive from bone marrow are detected, they will be analyzed to determine whether they are heritably muscle cells: by giving rise to myogenic clones in vitro and by contributing to host muscle fibers in vivo. Whether BMDC are reprogrammed to function as mononucleate satellite cells by fusion with host cells or manifest inherent plasticity in diverse environments will be investigated.
Specific Aim 3 will apply novel signal transduction assays, which we developed, to the cells, receptors, and ligands identified in Specific Aims 1 and 2. The proposed studies will enhance our understanding of muscle development and regeneration postnatally. An understanding of the biological basis for mobilizing, recruiting, and converting specific bone marrow derived cells to contribute to functional muscle fibers is not only of fundamental interest, but may also lead to novel therapies for muscle diseases. ? ? ?
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