There is a rapidly growing body of evidence that Mller glia can are a source of retinal progenitors to promote neural regeneration. Many studies have demonstrated that Mller glia can become proliferating progenitor cells in the retinas of different vertebrate species. Most reports have studied Mller glia-derived progenitors in acutely damaged retinas. However, little is known about the mechanisms that stimulate neurogenesis from Mller glia-derived progenitors in undamaged retinas or retinas undergoing slow, progressive degeneration. Furthermore, the regeneration of retinal neurons in warm-blooded vertebrates is limited compared to that seen in cold-blooded vertebrates. Therefore, the identification of the secreted factors and signaling pathways that block or stimulate neural regeneration from Mller glia-derived progenitors is crucially important to developing new therapies to treat degenerative diseases of the human retina. We have obtained compelling novel preliminary data indicating that Fatty acid-binding proteins (FABPs) and endocannabinoids impact the de-differentation and reprogramming of Mller glia into proliferating, neurogenic retinal progenitors in chicks and mice. We will investigate how the phenotype and plasticity of the Mller glia are regulated by FABPs and endocannabinoids in normal, damaged and growth factor-treated retinas. We will use a combination of pharmacological and genetic approaches to selectively activate or inhibit FABPs and endocannabinoid-signaling. We will compare and contrast how FABPs and endocannabinoid-signaling impacts the formation of Mller glia-derived progenitors in chick and rodent model systems with different inherent capacities for retinal regeneration. We expect that the completion of the experiments described in this proposal will provide significant new information regarding how mature Mller glia can be reprogrammed into Mller glia-derived progenitors that regenerate retinal neurons. Identification and understanding of the mechanisms that enhance the neurogenic potential of Mller glia is required to develop new therapies for sight- threatening diseases, such as glaucoma, retinitis pigmentosa and macular degeneration that involve the loss of retinal neurons.
A thorough understanding of the mechanisms that regulate the functions of retinal glial cells is crucially important to the development of new therapies to treat sight-threatening diseases of the eye. Retinal Mller glia are known to have the potential to become neurogenic progenitor cells. Identification and understanding the mechanisms that regulate the ability of Mller glia to reprogram into proliferating, neurogenic progenitors is key to developing new therapies to treat degenerative diseases. This proposal seeks to identify the important factors and pathways that control the ability of Mller glia to become proliferating progenitors and produce new functional neurons.