Genetic & Epi-Genetic Regulation of Muscle Regeneration

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DESCRIPTION (provided by applicant): The candidate plans to complement her achievements in the field of stem cell biology by developing new skills and a profound understanding of the complex science of DNA repair. To achieve this goal, the candidate will use help of Dr. Phil Hanawalt, renown in the field of DNA repair and a dynamic research environment provided by Dr. Tom Rando. The knowledge, skills and collaborations obtained during the initial mentored period will facilitate the career of an independent investigator in the new field of science. Scientifically, this award will give insight into the biology of progenitor cells in normal and aged tissues and provide novel practical solutions in tissue repair. This work will characterize the molecular mechanisms regulating regeneration of skeletal muscle and will investigate why repair deteriorates with age. Adult muscle regenerates due to the activity of satellite cells. With age, the regeneration capacity and muscle strength diminish and inflammatory-related pathologies increase. Biology of satellite cells is controlled, based on preliminary data, by the Notch and Wnt pathways that are active in young muscle cells, but not in old. The proposed work will study why Notch and Wnt signaling that are required for muscle regeneration are lacking after injury in aged muscle. The hypothesis is that in the adult muscle (comprised of terminally differentiated myotubes and quiescent satellite cells), many genes remain silent, and since DNA repair is not efficient in non-transcribed loci, DNA damage accumulates with time in these genes. When these previously silent loci are activated in response to muscle injury, the accumulated DNA damage interferes with transcription and results in the loss of cell function. We will investigate if muscle cells accumulate DNA damage with age and will test a potential molecular link between a quiescence- or differentiation-related decline in DNA repair and the injury-induced expression of Notch and Wnt pathway members. Complimenting this main research goal, we will perform a young-versus-old gene array analysis of genes activated by muscle injury in order to provide more candidates for the DNA repair studies and to identify novel genes regulating muscle regeneration. This work will help to understand postnatal myogenesis and is likely to have therapeutic value for the enhancement of regeneration in adult tissues.