The focus of this grant is to determine whether the transition from bone marrow to muscle occurs physiologically and can be enlisted in the treatment of muscle deficits associated with aging and disease. The finding that hematopoietic stem cells within bone marrow, bone marrow derived cells (BMDC), provide a reservoir of """"""""stem cells"""""""" that can be enlisted to contribute to the repair of muscle damage is now well established. Cell fate can be readily monitored by transplantation of green fluorescent protein (GFP) labeled bone marrow into irradiated wild-type donor mice. Alternatively, bone marrow transplant and concomitant irradiation can be bypassed by conjoining GFP+ mice with wild-type mice, a procedure known as parabiosis, which leads to blood chimerism. These two approaches will be used to address the following specific aims.
Specific Aim 1 will determine whether the whole body irradiation, cell mobilization, and the cytokine storm associated with a bone marrow transplant are prerequisites of the contribution of BMDC to muscle. Does muscle damage alone suffice? In addition to inducing acute damage by administration of toxins, physiologically induced damage will be analyzed, such as forced exercise on a treadmill, increased demands on a specific muscle by removing its neighbor, and the induction of ischemia in hind limb muscle.
Specific Aim 2 will determine whether the BMDC can participate in myogenesis in a sufficiently robust manner to induce a phenotypic and functional change. Does the selective pressure that accompanies muscle loss create a demand for these cells which can be fulfilled by BMDC? Four well characterized genetic models of muscular dystrophy will be tested. In addition, macrophages, which naturally accumulate at sites of muscle degeneration, will be genetically engineered to deliver factors which may enhance the BMDC contribution to muscle and functional recovery from dystrophy.
Specific Aim 3 will determine whether mice that have diminished stem cell reserve and age prematurely (telomerase null or progeric lamin-a mutant), incorporate BMDC into their muscle and other tissues. Can a transplant of wild-type BMDC replenish stem cell reserve and result in improved histology and function? In addition, the mdx dystrophic mouse will be bred with telomerase null mice to exacerbate their dystrophic phenotype. Taken together, these studies will determine whether the transition from bone marrow to tissues such as muscle occurs naturally, can be enhanced by three different physiological damage paradigms, and can be employed in the treatment of muscle wasting and other conditions associated with aging.
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