Grants and Contracts Details
Description
CHD7 (Chromodomain helicase DNA-binding 7) is an ATP-dependent chromatin
remodeling protein that has critical functions in neurogenesis and neural crest cell
development. Pathogenic variants in CHD7 are the most common cause of CHARGE
syndrome, a complex genetic syndrome characterized by ocular coloboma, heart
abnormalities, choanal atresia, retardation of growth, genitourinary defects, and hearing
loss, as well as other developmental defects. Although some studies have examined the
molecular basis for the early ocular defects (such as coloboma) resulting from CHD7
pathogenic variants, it is not known whether there is a continuing requirement for CHD7
in the developing retina once ocular morphogenesis is complete. We have recently
shown that CHD7 is robustly expressed in subsets of newly differentiated retinal cell
types, including rod and cone photoreceptors, as well as in proliferating retinal
progenitor cells. Furthermore, zebrafish and mouse Chd7 mutants display reductions in
cone photoreceptor number and abnormally small photoreceptor outer segments,
suggesting a critical role for CHD7 in photoreceptor differentiation and outer segment
morphogenesis. We hypothesize that the chromatin remodeling function of CHD7 is
necessary for the transcriptional activation of genes promoting retinal cell type
differentiation and genes involved in photoreceptor outer segment morphogenesis. In
this proposal, we will test this hypothesis through a combination of zebrafish and mouse
genetics, transcriptomic and epigenomic analyses, and studies of human retinal
organoids and human retinal imaging. Results from these studies will contribute to our
understanding of the genetic and epigenetic regulation of retinal cell type development
as well as the pathogenesis of visual system defects associated with CHARGE
syndrome.
Status | Active |
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Effective start/end date | 9/30/23 → 7/31/27 |
Funding
- National Eye Institute: $1,254,804.00
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