Upon injury, skeletal muscle satellite cells have the remarkable ability to quickly replicate to replace damaged muscle. The molecular signaling pathways that regulate skeletal muscle regeneration are largely unknown but may provide insight into therapeutic approaches for the treatment of muscle regeneration and skeletal muscle diseases. Recent studies suggest that muscle-specific microRNAs (miRNAs) may regulate muscle cell proliferation, differentiation and stress responsiveness. MiRNAs are a recently discovered class of small non-coding RNAs which are important in post-transcriptional gene silencing and involved in many biological processes including muscle development. The short-term objective of this application is to identify miRNAs which regulate myogenic progenitor cell (MPC) proliferation and differentiation to determine the regulatory roles of miRNAs in muscle regeneration. My long-term goal is to develop an independent research career and to establish an externally-funded program studying the molecular mechanisms underlying muscle regeneration to develop novel therapeutics to treat muscle-related diseases. Using a highly sensitive and reproducible quantitative real-time PCR-based array technology, my preliminary studies have identified multiple miRNAs that are differentially expressed during in vitro MPC proliferation and differentiation. Distinct miRNA expression patterns were observed at different stages of MPC differentiation. I hypothesize that miRNAs influence the replication vs. differentiation decisions of MPC, thereby playing critical roles in muscle regeneration. I will test the hypothesis using the following specific aims: 1) Determine the biological effects of differentially expressed miRNAs on in vitro MPC proliferation and differentiation;2) Identify miRNAs differentially expressed during in vivo muscle regeneration;and 3) Determine the biological effects of individual miRNAs on in vivo muscle regeneration. Studies that enhance our understanding of MPC proliferation, differentiation and muscle repair will be useful for therapeutic applications directed toward muscle diseases and tissue engineering. This proposal will investigate novel molecular pathways that may be important in influencing muscle regeneration. Successful completion of these studies will provide additional training in muscle biology and use of animal models that will enable my transition into being an independent investigator while demonstrating that miRNAs could become therapeutic targets for muscle injury and diseases.
Understanding the regulatory roles of microRNAs during muscle cell growth and differentiation may reveal novel molecular pathways underlying muscle regeneration and assist in developing novel therapeutics to treat muscle-related diseases and enhance tissue engineering strategies.
| Guo, Yingqiu; Chen, Yongxin; Carreon, Stephanie et al. (2012) Chronic intermittent ethanol exposure and its removal induce a different miRNA expression pattern in primary cortical neuronal cultures. Alcohol Clin Exp Res 36:1058-66 |
| Chen, Yongxin; Melton, David W; Gelfond, Jonathan A L et al. (2012) MiR-351 transiently increases during muscle regeneration and promotes progenitor cell proliferation and survival upon differentiation. Physiol Genomics 44:1042-51 |
