Progressive cell death in retinal degenerations causes visual impairment and blindness. In human retinas, there is little or no recovery of lost neurons in such conditions. For my career, I intend to study how to improve or preserve vision in retinal degenerative diseases by stimulating endogenous mechanisms. To do this, I plan to continue my rigorous postdoctoral training in the retinal regeneration field at the University of Washington under the supervision of Dr. Thomas Reh. Dr. Reh is an excellent mentor for this proposal, having expertise and experience in retinal regeneration and in guiding scientists into academic positions. With his mentorship, I will study whether forced expression of Ascl1 in retinal Muller glia promotes regeneration of new neurons in damaged mouse retinas. Retinas of non-mammalian vertebrates, such as zebrafish, show a robust regenerative response following injuries, which leads to complete restoration of lost neurons. This regenerative response includes dedifferentiation, proliferation, and neural differentiation of Muller glia. Identifying factors that can promote retinal regeneration in the mammalian retina may one day lead to the development of novel regenerative therapies for retinal degenerations. One factor that is important for regeneration in fish retina is the proneural transcription factor Achaete-scute homolog 1 (Ascl1/Mash1). However, Ascl1 is not upregulated after damage in mouse retinas. Therefore, we hypothesize that failure of Ascl1 expression in mature mouse Muller glia after damage limits their ability to regenerate new neurons. To test this, I will force the expression of Ascl1 in mouse Muller glia and determine whether this can promote regeneration.
In Aim 1, I will test whether expression of Ascl1 specifically in Muller glia promotes their proliferation in vivo.
n Aim 2, I will investigate whether expression of Ascl1 in Muller glia promotes their neural differentiation and functional regeneration of the mouse retina in vivo after light or NMDA damage. Together, the proposed studies will enrich our current understanding of factors limiting retinal regeneration in mammalian retinas, and help develop therapeutic approaches aimed at stimulating endogenous repair mechanisms.
Retinal degenerations cause visual impairment and blindness. Regenerative therapy is an attractive approach to replace lost photoreceptors and other retinal neurons to restore vision in such conditions. In this proposed study, we will attempt to stimulate endogenous repair mechanisms in mice with induced retinal degenerations, to determine whether this will promote functional recovery.
|Ueki, Yumi; Wilken, Matthew S; Cox, Kristen E et al. (2015) Transgenic expression of the proneural transcription factor Ascl1 in MÃ¼ller glia stimulates retinal regeneration in young mice. Proc Natl Acad Sci U S A 112:13717-22|
|Ueki, Yumi; Wilken, Matthew S; Cox, Kristen E et al. (2015) A transient wave of BMP signaling in the retina is necessary for MÃ¼ller glial differentiation. Development 142:533-43|