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 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 and in vivo. (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 have been assembled. The biological functions of these genes will be investigated and the collection will 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.
Diseases of the retina result in impairments of sight ranging from loss of visual acuity to total blindness. These diseases result from degenerated or otherwise nonfunctional retinal tissue. An exciting potential therapeutic approach for treatment of these diseases involves the replacement of degenerated or nonfunctional retinal tissue with healthy tissue derived from retinal stem cells. The retinal homeobox (Rx) gene is expressed in retinal progenitor and stem cells. The subject of this research proposal is investigation of the genetic mechanisms governing the development and maintenance of retinal progenitor cells.
|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|
|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|
|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|
|Martinez-de Luna, Reyna I; Moose, Holly E; Kelly, Lisa E et al. (2010) Regulation of retinal homeobox gene transcription by cooperative activity among cis-elements. Gene 467:13-24|
|Pan, Yi; Martinez-De Luna, Reyna I; Lou, Chih-Hong et al. (2010) Regulation of photoreceptor gene expression by the retinal homeobox (Rx) gene product. Dev Biol 339:494-506|
|Wilson, Jonathan M; Martinez-De Luna, Reyna I; El Hodiri, Heithem M et al. (2010) RNA helicase Ddx39 is expressed in the developing central nervous system, limb, otic vesicle, branchial arches and facial mesenchyme of Xenopus laevis. Gene Expr Patterns 10:44-52|
|Moose, Holly E; Kelly, Lisa E; Nekkalapudi, Srivamsi et al. (2009) Ocular forkhead transcription factors: seeing eye to eye. Int J Dev Biol 53:29-36|
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