Genetic Modification to Harness the Regenerative Power of the African Spiny Mouse

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PROJECT ABSTRACT A fundamental goal of regenerative medicine is to replace fibrosis and scarring in damaged mammalian tissues with functional tissue. Thus far there has been very little progress towards this goal because of a lack of an adult mammalian model system that demonstrates functional regeneration, and instead the typical response of damaged mammalian skin is to form a hairless, collagenous scar. However, recent studies revealed that African spiny mouse (Acomys), following full thickness skin removal, can regenerate all the tissues removed: the epidermis, hair, sebaceous glands, erector pili muscles, dermis and skeletal muscle of the panniculus carnosus, all without scarring. In our experiments to date characterizing the differences between regenerating Acomys skin wounds and scarring Mus skin wounds, we have identified many molecular differences but we have no real handle on what exactly are responsible for regeneration vs scarring. To reveal molecular mechanisms underlying this remarkable capacity of Acomys to regenerate normal tissue, the scientific community needs a way to modify genes in the animals. For instance, we previously identified that collagen type III is particularly abundant in Acomys skin regeneration, whereas Mus exhibits a much higher ratio of collagen type I to type III during wound scarring1. However, we do not know that how this abundant collagen type III plays a role in a higher regenerative capacity of Acomys. In the present proposal, we will knockout the Col3a1 gene within Acomys fibroblasts as well as the whole animals as an exemplar with which to study the role of specific genes in higher wound repair capacity of the animal. The establishment of an efficient gene editing method with Acomys will open a revolutionary new avenue for mammalian regeneration research.