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Path-Immuno - Graeme Mardon Lab

Houston, Texas

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Path-Immuno - Graeme Mardon Lab
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Graeme Mardon Laboratory

A scanning electron micrograph of an adult Drosophila compound eye is shown with a microarray image data overlayA scanning electron micrograph of an adult Drosophila compound eye is shown with a microarray image data overlay. This image was used for the cover art for our most recent publication in Genome Research (April 2006)

Research Interests

Molecular Mechanisms of Retinal Development

The primary goal of our research is to understand molecular mechanisms of retinal development with the ultimate goal of improving our ability diagnose, prevent, and treat human retinal disease. To this end, we are using three approaches, all in collaboration with Dr. Rui Chen, in the Department of Molecular and Human Genetics.

  • The first two approaches use the mouse Mus musculus and the fruit fly Drosophila melanogaster as animal model systems to identify and determine the function of conserved genes required for normal retinal development.
  • The third approach is to map new human retinal disease genes. In spite of substantial differences between vertebrate and insect retinal morphology, genetic mechanisms of retinal development have been conserved for more than 500 million years.

Drosophila Project

Thus, study of the molecular and genetic pathways controlling Drosophila eye development has provided a valuable set of tools with which to decipher the development and function of the vertebrate retina. Our main Drosophila project uses a combinatorial approach of genetics, genomics, and computational biology to dissect the roles of eyes absent and sine oculis , two conserved genes controlling retinal determination and differentiation. We are using ChIP-Seq to identify direct targets of the Sine oculis homeobox transcription factor as well as several other key proteins required for normal retinal development.

In addition, we are using a novel genomic rescue strategy to definitively dissect the in vivo function of several conserved domains in these proteins. Finally, we are using transcriptional regulation of eyes absent as a paradigm for studying the relationship between chromatin remodeling and developmental regulation of this key retinal gene.

Mouse Knockout and Knockin Technology

In our second approach, we are using mouse knockout and knockin technology to determine the function of several new genes whose expression is specifically enriched in the retina during development. These genes include a histone demethylase, a protein phosphatase, a phospholipase, a protein kinase, and a transcription factor. Germline transmission of several knockout constructs have already been generated and we expect to have targeted knockouts of all genes within the next year. Complete functional studies will be conducted and several new projects are available.

Leber Congenital Amaurosis

Our third project is to map new human disease genes associated with Leber Congenital Amaurosis (LCA), the most common cause of blindness in children. While there 12 genes known to be associated with LCA these account for only about 70 percent of all cases. Therefore, several new loci remain to be identified. In collaboration with Drs. Chen, Lupski, and Lewis, we are using whole genome linkage studies to map new LCA genes in 29 families. We have already identified one new putative disease gene and expect several more in the near future. Mouse models will be created for each new disease gene identified.

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