The role of the bHLH transcription factor NeuroD in regulating photoreceptor rege

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Photoreceptor degenerative diseases lead to permanent vision loss in humans. The development of regenerative therapies that restore vision in humans will require substantial advances to the current understanding of mechanisms of stem cell-based regeneration. The long-term goal of our research is to understand the molecular mechanisms that govern stem cell-based neuronal regeneration in the retina, using zebrafish as a model organism. A next step in achieving this goal, and the overall objective of the present research, is to discern the role of NeuroD in photoreceptor regeneration. This objective will be accomplished by testing the central hypothesis that NeuroD is a key molecule in signaling pathways that control photoreceptor regeneration. This hypothesis will be tested by accomplishing 2 specific aims. Specific Aim 1 will test the specific hypotheses that 1) NeuroD is required for photoreceptor progenitors to exit the cell cycle during photoreceptor regeneration and 2) NeuroD function is mediated via downstream genes that are essential for photoreceptor regeneration. This will be accomplished by comparing photoreceptor regeneration, cell proliferation, and expression of downstream genes in regenerating retinas between normal and NeuroD-deficient retinas. Specific Aim 2 will test the specific hypothesis that NeuroD mediates the function of canonical Wnt signaling in photoreceptor progenitors during photoreceptor regeneration. This will be accomplished by comparing neuroD expression and localization of the canonical Wnt effector (?-catenin), and determining the effects of canonical Wnt signaling manipulation on neuroD expression. This research will provide a significant and important step toward understanding pathways regulating photoreceptor regeneration in vertebrates, and will contribute to our fundamental knowledge of factors regulating stem cell-based regeneration in the nervous system. This contribution will provide critical information applicable to the development of regenerative therapies aimed at treating human retinal disease.