Thomas Rando

Research/Lab website:   http://www.stanford.edu/~casco/

Molecular mechanisms of muscle progenitor cell activation: Notch and Wnt signaling

A major interest of the lab is the mechanism by which muscle stem cells are activated to form new muscle during growth, in response to injury, or in disease states. Our recent studies have focused on the Notch and Wnt signaling pathways in these processes. We have found that activation of the Notch signaling pathway is critical to the transition of muscle stem cells ("satellite cells") from a quiescent state to one of active proliferation. The regulation of Notch signaling by its inhibitor Numb appears to determine lineage progression and cell fate determination. Numb is found to be localized asymmetrically in dividing progenitor cells and may be involved in the process of satellite cell self-renewal. We have recently found that activation of the Wnt signaling pathway occurs during muscle injury when satellite cells are proliferating. There appears to be an antagonistic interaction between Notch and Wnt signaling in activated satellite cells during this process. Furthermore, we have found that the age-related impairment of muscle regeneration is due to a decline in effective Notch signaling, manifested initially as a failure of injured muscle to upregulate the Notch ligand, Delta. We are currently exploring further the regulation of the Notch and Wnt signaling pathways during satellite cell activation, the mechanisms underlying the transcriptional control of Delta expression, and epigenetic processes that may account for age-related changes in these pathways. Our near-term goals are to identify the key signaling processes that control satellite cell activation and lineage progression in order to enhance muscle regeneration.

Gene therapy for muscle diseases

Another major focus in the laboratory is gene therapy approaches to the treatment of Duchenne muscular dystrophy (DMD), a degenerative disease of muscle due to mutations in the dystrophin gene that lead to an absence of dystrophin protein in muscle. We have been involved in the development of a novel gene therapy approach using oligonucleotide vectors (DNA vectors or chimeric RNA/DNA vectors) to modify genomic DNA and thus explore the possibility of true gene repair rather than gene delivery.

Muscle Cell Growth and Differentiation

We are also interested in the molecular and biochemical mechanisms of muscle cell differentiation and fusion. During this process mononucleated myoblasts undergo both profound morphological and biochemical changes in which the mononucleated cells fuse to become multinucleated myotubes and express muscle-specific genes that are responsible for the phenotype of mature muscle cells. This phenotype includes the specializations at the neuromuscular junction, the excitation-contraction coupling machinery, and the major contractile apparatus that allows muscle to generate force. We have focused on the early stages of that differentiation process, studying the role of integrin signaling in the control of myoblast shape and fusion, the downstream integrin signaling mediated by protein kinase C (PKC) and its substrate MARCKS, and the ontogeny of both sarcomeres and costameres during myogenesis.