Transcriptome atlas at single cell level across the main phases of photoreceptor degeneration in Retinitis Pigmentosa

The most recent technological advances in transcriptome analyses provide unprecedent opportunities for studying disease mechanisms andpave the way towards the development of effective treatments. Single cell RNA sequencing allows the identification of gene expressionchanges in specific cell types in the affected tissue during the progression of a disease. Such highly detailed level of information allows todissect differential responses to the disease process of the cells composing an organ and provide us with the possibility of identifying newbiomarkers and of developing drugs for specific targets together with precise delivery systems. Altogether this information is necessary fordeveloping novel therapeutic opportunities. In this project we propose to perform transcriptomics at single cell level, analyse and validate the results for a rare disease leading toblindness, i.e. Retinitis Pigmentosa (RP). RP is an inherited disease which causes degeneration of photoreceptor cells in the retina and canbe caused by mutations in more than 100 different genes. While few gene-specific therapies are available, the majority of patients does nothave access to any effective treatment. The devise of gene-independent therapeutic approaches is thus needed to overcome the highgenetic heterogeneity that underlies RP. To address this medical need, it is necessary to gain further insight into the pathogenic mechanismsthat eventually lead to photoreceptor degeneration in order to highlight genes and pathways that can represent relevant therapeutic targets.To fill the present gap of knowledge on the pathogenic events at the basis of this condition, we propose to analyse single cell transcriptomicsat three relevant stages of photoreceptor degeneration in two well recognized murine models of RP caused by mutations in different genes.This will be the first study applied to RP with the goal of comparing gene expression with a time course approach at single cell level. Theproject will be carried out by two Units with longstanding complementary expertise in the field of genetics of retinal disease, both fromfunctional genomics /bioinformatics and from retinal cell biology points of view. We expect to identify gene expression changes common todifferent mutations causing RP, as well as mutation-specific changes. The time course nature of this study is expected to lead to informationon molecular pathways relevant in the progression of the disease and representing ideal targets for gene/mutation-independent approachesthat can be applied to a significant fraction of RP patients.