Adult muscle stem cells (MuSC), also known as satellite cells, are the main source skeletal muscle regeneration. MuSC exist in healthy adult tissues in a quiescent state, and upon stress or injury they are activated to proliferate and generate large numbers of progenitors to repair the damaged tissue. Although the balance between quiescence and activation is a critical switch in MuSC function, the molecular mechanisms regulating this transition are still largely unknown. An improved understanding of the networks regulating MuSC function would facilitate their use in regenerative medicine for the development of therapeutic approaches for muscle wasting diseases. Our preliminary findings indicate that STAT3 regulates MuSC proliferation as well as plays a direct role in the transcriptional activation of the bHLH myogenic regulatory factor MyoD, a key event as MuSC exit the quiescent state. Upon cytokine stimulation, STAT3 is phosphorylated by JAK kinases, translocates to the nucleus and binds DNA to activate the transcription of target genes. The focus of this proposal is to investigate the role of the STAT3 in MuSC self-renewal, activation and myogenic commitment and to identify its relevant downstream targets. Our research will take advantage of the following tools: (1) Loss of function studies in conjunction with time-lapse microscopy, to monitor MuSC activation in situ, (2) Chromatin ImmunoPrecipitation (ChIP), ChIPseq and microarray gene expression profiling, in order to identify novel STAT3 downstream targets in MuSC, (3) Conditional genetic ablation of STAT3 in MuSC, in order to evaluate its role in MuSC self-renewal and maintenance in vivo in the intact animal, and (4) Human MuSC isolated from patients, to determine whether the critical role of STAT3 in MuSC function is conserved in between the two species. Together, these studies would identify a direct functional interaction between STAT3 and MyoD, and further extend our knowledge of the STAT3 regulatory network in MuSC activation. Finally, these findings would aid in the development of strategies aimed at promoting muscle stem cell-mediated tissue regeneration to ameliorate muscle-wasting diseases.
The proposed studies are relevant to efforts for developing therapeutic approaches for muscle-wasting diseases. We will dissect molecular mechanisms regulating skeletal muscle stem cell activation, thus providing a foundation of knowledge on how muscle stem cells coordinate tissue regeneration and how they can rapidly respond to stress or injury and repair the damaged tissue. Finally, these studies will suggest novel targets that will aid in the development of novel therapies to ameliorate muscle-wasting diseases.
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