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.

Public Health Relevance

Human retinal diseases that destroy light-sensitive photoreceptor cells can result in permanent blindness, because the human retina cannot regenerate these cells. The fish retina does regenerate photoreceptors, however, and we therefore use zebrafish as a model system to investigate specific molecular mechanisms that control photoreceptor regeneration. In this application we hypothesize that the bHLH transcription factor NeuroD is a key molecule in this process and propose experiments to understand its function - knowledge that is applicable to the development of regenerative therapies that treat human retinal disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32EY023129-02
Application #
8685012
Study Section
Special Emphasis Panel (ZRG1-F05-R (20))
Program Officer
Agarwal, Neeraj
Project Start
2012-12-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$62,030
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109