Project description:Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of accurate and color vision and ultimately blindness. In RP, a vast number of mutations are affecting the structure and function of rod photoreceptors while cones remain mutation-free. Once majority of rods have degenerated cones are dying secondarily due to the increased oxidative stress, inflammation and loss of structural and nutritional support normally provided by rods. Here we demonstrated that secondary cone cell death in animal models for RP is governed by an increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at a late stage of the disease, when majority of rods have already degenerated, is sufficient to delay cone death and support long-term cone survival. Surviving cones are retaining functionality and are mediating light-driven ganglion cell responses. RNA-seq analysis of surviving cones demonstrated that HDAC inhibition affords multi-level protection trough regulation of different prosurvival pathways including MAPK, PI3K-AKT and autophagy. These study suggest a unique possibility for targeted pharmacological protection of both primary degenerating rods and mutation-free secondary dying cones and creates hope to maintain vision in RP patients independent of the disease stage.
Project description:Purpose: To identifiy mRNA changes in retinitis pigmentosa (RP) cone photoreceptors with Txnip overexpression treatment, which improved RP cone survival and visual acuity. Methods: two RP mouse strains, rd1 and Rho-/-, were injected with AAV-Txnip or AAV-H2BGFP control subretinally at P0. Retinas were dissected out at P21 for rd1 and P90 for Rho-/-. 1,000 H2BGFP labeled cones per retina sample were FACS sorted out, and subject for RNA-sequencing. Results: >1,400 genes in P21 rd1 and >700 genes in Rho-/- were found differentially expressed with Txnip treatment. Conclusions: 25 genes are in common between P21 rd1 and P90 Rho-/- with Txnip treatment. On this list, notably, three mitochondrial Electron Transport Chain (ETC) genes were up-regulated.
Project description:Recessive retinitis pigmentosa (RP) is often caused by nonsense mutations that lead to low mRNA levels as a result of nonsense-mediated decay. Some RP genes are expressed at detectable levels in leukocytes as well as in the retina. We designed a microarray-based method to find recessive RP genes based on low lymphoblast mRNA expression levels Keywords: Recessive mutations; mRNA expression; nonsense mediated-decay; retinitis pigmentosa; lymphocyte; Affymetrix genechip Human Genome U133Plus2.0.
Project description:In inherited retinal disorders such as retinitis pigmentosa (RP), rod photoreceptor-specific mutations cause primary rod degeneration that is followed by secondary cone death and loss of high-acuity vision. Mechanistic studies of retinal degeneration are challenging because of retinal heterogeneity. Moreover, the detection of early cone responses to rod death is especially difficult due to the paucity of cones in the retina. To resolve heterogeneity in the degenerating retina and investigate events in both types of photoreceptors during primary rod degeneration, we utilized droplet-based single-cell RNA sequencing in an RP mouse model, rd10.
Project description:A Drosophila mutant for the splicing factor Prp31 was generated and characterized as a model for Retinitis pigmentosa 11. The transcriptome of the mutant was compared to the genetic control white.
Project description:Experiment to examine the miRNA profiles in the retina compared to the brain and other body regions. A comparison of a wild type C57 mouse retina versus a retina from a mouse model of retinitis pigmentosa (Pro347Ser) was under taken.
Project description:Retinitis pigmentosa is an inherited disease with sequential retinal degeneration of rod then cone photoreceptors leading to blindness. As in this human syndrome the rd1 mouse model carries a recessive mutation in the rod-specific cGMP phosphodiesterase beta subunit gene leading to rod followed by cone photoreceptor death. The cascade of early events leading to the induction of rod cell death through apoptosis remains unknown. We report a differential whole-genome expression profiling analysis of the wild-type and rd1 mouse retinal transcriptional program using high-density oligonucleotide microarrays with a time series experiment spanning the entire rod photoreceptor degeneration process. Among the 1252 genes found to be significantly differentially expressed, a key group of 19 loci showed distinct differences in expression early in development, suggesting that these genes of clinical interest may play a fundamental role in the induction of the rod photoreceptor degeneration.
Project description:Single-cell RNA-seq of mouse WT retinas and two Nr2e3 mutant retinas, ∆27 and ∆E8 (containing a 27 nucleotide in-frame deletion or a complete exon 8 deletion, respectively). The ∆27 retinas were used as a model for enhanced S-cone syndrome phenotype in humans, while the ∆E8 retinas show a progressive retinal degeneration similar to human retinitis pigmentosa patients. This data was used to explore the role of Nr2e3 in cone and rod photoreceptor differentiation.