About 10 million Americans suffer from age-related macular degeneration (AMD) or diabetic retinopathy, and prevalence is expected to increase 50-75% by 2030. These diseases are associated with rod and/or cone photoreceptor cell death, which causes permanent vision loss. Current therapies can limit photoreceptor loss, but do not restore vision to blind patients. To overcome this, researchers have attempted to generate new photoreceptors from stem cells and transplant them into diseased retinas. While promising, this approach remains too inefficient and time-consuming to be clinically feasible. This is because the earliest events in photoreceptor development- competence (cell fate potential) and specification (cell fate commitment) - are poorly understood. The project objective is to understand these early events in mice; an excellent model system for human retinal development.
The first aim of this project is to determine how a key early photoreceptor gene, Blimp1, is regulated during development. This will be done by investigating the requisite sequence from a recently discovered Blimp1 enhancer with high-throughput organotypic culture assays. Using a proteomics approach, the transcriptional regulators that bind to the Blimp1 enhancer will be discovered. These factors will then be investigated for their effect on Blimp1 expression and photoreceptor fate specification.
The second aim of this project is to characterize how photoreceptor competence is regulated during development. The temporal aspects of photoreceptor competence will be investigated by narrowly altering competence in specific cell types, for different lengths of time, and at different stages of development. This project will uncover the mechanisms that regulate early events in photoreceptor development; information that is critical for the successful design and implementation of photoreceptor cell replacement therapies. These therapies have tremendous potential to reverse blindness in millions of people world-wide.

Public Health Relevance

To successfully implement new treatments that reverse blindness, we must first understand how rod and cone photoreceptors are formed. In this project, we will uncover how the earliest events in photoreceptor development are controlled. Our results will directly promote efforts to replace lost rods and cones in human patients, which have the potential to restore vision to the blind.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY024272-05
Application #
9462137
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Neuhold, Lisa
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Goodson, Noah B; Nahreini, Jhenya; Randazzo, Grace et al. (2018) Prdm13 is required for Ebf3+ amacrine cell formation in the retina. Dev Biol 434:149-163
Park, Ko Uoon; Randazzo, Grace; Jones, Kenneth L et al. (2017) Gsg1, Trnp1, and Tmem215 Mark Subpopulations of Bipolar Interneurons in the Mouse Retina. Invest Ophthalmol Vis Sci 58:1137-1150
Mills, Taylor S; Eliseeva, Tatiana; Bersie, Stephanie M et al. (2017) Combinatorial regulation of a Blimp1 (Prdm1) enhancer in the mouse retina. PLoS One 12:e0176905
Groman-Lupa, Sergio; Adewumi, Joseph; Park, Ko Uoon et al. (2017) The Transcription Factor Prdm16 Marks a Single Retinal Ganglion Cell Subtype in the Mouse Retina. Invest Ophthalmol Vis Sci 58:5421-5433
Brzezinski, Joseph A; Reh, Thomas A (2015) Photoreceptor cell fate specification in vertebrates. Development 142:3263-73