Retinal Damage and Regeneration in the African Spiny Mouse (Acomys cahirinus): A Novel Mammalian Model for Translational Research

II. Scientific summary The loss of sight that results from diseases like retinitis pigmentosa (RP) and macular degeneration is especially devastating because it is currently irreversible. Therapeutic strategies such as gene therapy and cell-based transplantation hold great potential, but are only an option for a small group of patients, and several technical and theoretical challenges must be overcome before they become widely available. One complementary approach to treating retinal degenerative diseases is to find ways to promote endogenous regeneration in the diseased or damaged retina. Across the animal kingdom, several vertebrate species, including fish, amphibians, and reptiles, are capable of regenerating their retinal neurons in response to acute injury. Research into the mechanisms regulating retinal regeneration in these species has yielded valuable information and highlighted the critical role of retinal Müller glia as the source of regenerating cells. However, to translate these findings into therapies, it would be helpful to incorporate an animal model that more closely mirrors human ocular physiology to probe the regenerative potential of the mammalian retina. In recent years, spiny mice (Acomys) have become the focus of intense research for their ability to heal skin wounds without scars. Further studies have revealed that spiny mice exhibit regenerative capacity beyond the skin, in tissues such as the heart and the spinal cord. This raises the question of whether these mammals can regenerate retinal neurons in response to damage. During the previous funding period, we demonstrated that the spiny mouse retina mounts a pro-regenerative response to acute retinal damage, and that this response encompasses both Müller glia proliferation and the induction of neurogenic gene expression, neither of which are observed in the non-regenerating Mus musculus retina following damage. This positions Acomys as an ideal animal model with which to address longstanding questions about regenerative potential in the mammalian retina. One critical knowledge gap involves the role of innate immune cells and inflammation in the regenerative process. In fully regenerating species such as the zebrafish, acute retinal damage induces infiltration of activated microglia as well as inflammatory signaling via the Jack/Stat and TNF-alpha pathways; these immune responses are required to promote efficient retinal regeneration. In contrast, Jak/Stat signaling inhibits the neurogenic potential of Müller glia in the chick retina, and microglia suppress retinal regenerative responses elicited by forced expression of Ascl1 in Mus Musculus. By studying Acomys, a mammal with natural retinal regenerative capacity, we now have a unique opportunity to address these contradictory findings. To do this, we propose two specific aims: 1) we will ascertain whether microglial activation is required for the pro-regenerative program in Acomys retina following acute damage; and 2) we will determine how inflammatory signaling through the Jack/Stat and TNF- alpha pathways influences the Acomys pro-regenerative response. The results of our studies will address critical gaps in our understanding of how cross-talk between the immune system, inflammation, and Müller glial behavior shapes regeneration potential in the mammalian retina, and may identify promising avenues for promoting regeneration in human patients with retinal degenerative diseases.