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.
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.
|Brzezinski, Joseph A; Reh, Thomas A (2015) Photoreceptor cell fate specification in vertebrates. Development 142:3263-73|