Normal vision relies on the coordinated activity of numerous highly specialized cells organized within the eye and in projection areas within the brain. In the eye, the retina develops through a series of sequential cell differentiation steps tht culminate in the generation of the different retinal cell types properly organized within the laminated structure of the mature retina. A complex network of transcription factors and extracellular signaling molecules regulates this process. Although a number of the regulatory molecules that control fate specification and differentiation of retinal cells have been already identified, we are still far from a comprehensive understanding of the molecular mechanisms regulating retinal development. The long-term goal of this project is to identify key gene regulators of retinal progenitor cell differentiation in general and photoreceptor differentiation n particular. Within this framework, we have identified CTCF, a multifunctional transcriptional regulator previously unknown to participate in these phenomena, as a leading candidate in regulating several aspects of retinal cell differentiation. Based on our observations we have hypothesized that CTCF regulates the initial specification of neural retina progenitor cells from the pool of uncommitted progenitors within the optic vesicle, and promotes their subsequent survival and differentiation toward a photoreceptor lineage. We will use loss- and gain-of-function approaches, and their complementary phenoytype-rescue strategies, to investigate these hypotheses. These studies will contribute to a better understanding of the mechanisms driving retina development in normal and diseased conditions and to build up an integrated network of the molecules involved in this process. This knowledge in turn, is expected to have a significant impact on the potential prevention of developmental abnormalities of the retina and the development of feasible stem cell-based therapeutic treatments for retinal degenerative diseases.

Public Health Relevance

The studies carried out in this project will contribute to a better understanding of the mechanisms that regulate the development of the retina in normal and diseased conditions. This knowledge is of great clinical relevance because of its potential impact in the prevention of congenital abnormalities of the retina and the development of feasible stem cell-based therapeutic treatments for retinal degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY022631-01
Application #
8345015
Study Section
Special Emphasis Panel (BVS)
Program Officer
Neuhold, Lisa
Project Start
2012-08-01
Project End
2017-06-30
Budget Start
2012-08-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$405,000
Indirect Cost
$155,000
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Zhong, Xiufeng; Gutierrez, Christian; Xue, Tian et al. (2014) Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun 5:4047
Vergara, M Natalia; Gutierrez, Christian; O'Brien, David R et al. (2013) Ex vivo electroporation of retinal cells: a novel, high efficiency method for functional studies in primary retinal cultures. Exp Eye Res 109:40-50
Moshiri, Ala; Scholl, Hendrik P N; Canto-Soler, Maria Valeria et al. (2013) Morphogenetic model for radial streaking in the fundus of the carrier state of X-linked albinism. JAMA Ophthalmol 131:691-3