ABSTRACT¿:
Each year, millions of people lose their vision to chronic degenerative diseases like glaucoma,
retinitis pigmentosa, macular degeneration, and diabetic retinopathy. However, therapeutic
options for patients are remarkably limited, in part because the biological events underlying
these retinopathies are only starting to be understood. Glia can both mitigate and exacerbate
neurodegeneration, so understanding neuron-glia crosstalk during chronic stress-induced
conditions is an essential first step towards building more effective vision-saving tools. We have
developed an experimental pipeline that uncovers functional, cellular and molecular changes
during chronic light-induced degeneration and recovery. Our approach takes advantage of two
genetically amenable model systems, Drosophila and zebrafish, to probe for evolutionarily
deeply conserved, and hence fundamental, neuroprotective responses from endogenous radial
glia. Using non-invasive structure-function methods, coupled to histological and single-cell
RNAseq studies, we will test for conserved cellular and molecular events associated with
recoverable vs irrecoverable light damage. As proof-of-principle, we propose to define the
neuroprotective role for the transcription factor prospero (pros)/Prox1 in this experimental
paradigm. Pros/Prox1 is a pleiotropic factor implicated in diabetes, neural progenitor cell cycle
control, neuron-glia fate decisions, and regeneration in response to acute physical damage.
Preliminary and published studies reveal that Pros/Prox1 is enriched in fly and fish retinal glia,
and is required to prevent retinal degeneration. The successful completion of this R21 will
identify conserved Pros/Prox1-dependent glial response pathways that are at play during
light-induced degeneration. In the long-term, these studies will serve as the foundation for
developing screens to identify nodes of intervention for chronic retinal degenerative diseases.