Diseases of the retina result in impairments of sight ranging from loss of visual acuity to total blindness as a result of degenerated or otherwise nonfunctional retinal tissue. The retina develops from a set of multipotent progenitor cells, the specification, proliferation, and differentiation of which is dependent on a set of conserved genes. One of these genes, the retinal homeobox gene, Rx, is essential for regulation of retinal cell progenitor specification and proliferation. Even so, the genetic and molecular details of Rx activation and function are poorly understood. The long-term objective of this application is to gain an understanding of the role of Rx in eye development by elucidating the molecular mechanisms of Rx function and the components of the Rx genetic pathway. The following experimental approaches will be undertaken to achieve this objective. (1) To gain a better understanding of the genetic events leading to the activation of Rx, cis-acting elements and trans-acting factors that regulate Rx promoter activity will be identified and characterized. (2) To elucidate the molecular mechanism of Rx function, the involvement of conserved peptide domains encoded by Rx will be investigated in the context of an intact Rx-responsive promoter. (3) To gain a better understanding of Rx function at different phases of eye development, Rx target genes will be identified and characterized. A collection of candidate Rx target genes will be assembled by chromatin immunoprecipitation (CHIP) and a bioinformatics-based approach. The collection will then be refined to identify authentic Rx targets. The results of these experiments will lead to elucidation of upstream and downstream components of Rx genetic and biochemical pathways, which is essential to our understanding of the biological basis of eye development and disease. Additionally, identification of Rx genetic pathway components will expand the pool of candidate genes involved in eye development and human ocular birth defects. Finally, understanding the mechanisms by which Rx is involved in retinal progenitor cell specification and proliferation has profound implications for our abilities to manipulate and exploit retinal stem cells for novel therapeutic approaches involving the replacement of damaged or nonfunctional retinal tissue.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015480-02
Application #
6888014
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Hunter, Chyren
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$343,125
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
El-Hodiri, Heithem M; Kelly, Lisa E (2018) Visualization of Gene Expression Patterns by In Situ Hybridization on Early Stages of Development of Xenopus laevis. Methods Mol Biol 1797:325-335
Pan, Yi; Kelly, Lisa E; El-Hodiri, Heithem M (2018) Identification of retinal homeobox (rax) gene-dependent genes by a microarray approach: The DNA endoglycosylase neil3 is a major downstream component of the rax genetic pathway. Dev Dyn 247:1199-1210
Pan, Yi; Comiskey, Daniel F; Kelly, Lisa E et al. (2016) Regulation of photoreceptor gene transcription via a highly conserved transcriptional regulatory element by vsx gene products. Mol Vis 22:1421-1428
Kelly, Lisa E; Martinez-De Luna, Reyna I; El-Hodiri, Heithem M (2016) Autoregulation of retinal homeobox (rax) gene promoter activity through a highly conserved genomic element. Genesis 54:562-567
Bosse, Jennifer L; El-Hodiri, Heithem M (2016) Expression of the insulinoma-associated 1 (insm1) gene in Xenopus laevis tadpole retina and brain. Gene Expr Patterns 22:26-29
Kelly, Lisa E; El-Hodiri, Heithem M (2016) Xenopus laevis Nkx5.3 and sensory organ homeobox (SOHo) are expressed in developing sensory organs and ganglia of the head and anterior trunk. Dev Genes Evol 226:423-428
Fischer, Andy J; El-Hodiri, Heithem M (2014) Response to: Janssen et al., ""Human ciliary epithelia do express genes with retinal progenitor cell characteristics in vivo"". Exp Eye Res 129:183-4
Fischer, Andy J; Bosse, Jennifer L; El-Hodiri, Heithem M (2014) Reprint of: the ciliary marginal zone (CMZ) in development and regeneration of the vertebrate eye. Exp Eye Res 123:115-20
Martinez-De Luna, Reyna I; Kelly, Lisa E; El-Hodiri, Heithem M (2011) The Retinal Homeobox (Rx) gene is necessary for retinal regeneration. Dev Biol 353:10-8
Stanke, Jennifer; Moose, Holly E; El-Hodiri, Heithem M et al. (2010) Comparative study of Pax2 expression in glial cells in the retina and optic nerve of birds and mammals. J Comp Neurol 518:2316-33

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