Giamundo, Giuliana (2024) Modulation of cell clearance to preserve vision in inherited retinal diseases (IRDs). [Tesi di dottorato]

Documento PDF GIAMUNDO_GIULIANA_TESI_37_CICLO.pdf Visibile a [TBR] Amministratori dell'archivio Download (44MB) | Richiedi una copia

Abstract

Inherited retinal diseases (IRDs) are a group of diseases that result in severe vision loss or even blindness. Each retinal disease is caused by one or more defective genes. Despite IRDs are quite rare and can progress at different rates, many are degenerative and therefore the disease’s symptoms will worsen over time. There are many types of IRDs like Retinitis Pigmentosa (RP), Choroideremia (CHM) and Age-related macular degeneration (AMD). AMD is the most common cause of severe vision loss among people 50 and older. AMD, as well as all other retinal diseases, is often associated with an impaired function of the Retinal Pigment Epithelium (RPE), as this layer/structure is vital for the development, health, survival, and function of the adjacent retinal photoreceptors and choroid. A key process deteriorating in the RPE cells with aging is the degradation of damaged or misfolded proteins. These accumulates damaged proteins and undigested photoreceptors’ outer segment (POS), resulting in further accumulation of detrimental aggregates. These aggregated are most efficiently removed by autophagy, a process also known to be impaired in IRDs. The aggregates are therefore thought to be taken, via exocytosis, out of the RPE cells, where they can be involved in drusen formation. Recent studies, using multiple approaches including next generation sequencing technology and in situ hybridization analysis, have reported that miRNAs are involved in RPE development and differentiation in a variety of species. Considering that, GWAS and omics studies have demonstrated that miR-211 represent a risk allele and a marker for dry AMD. In light of this, using in vitro (HeLa, Arpe-19 and MEF cells) and in vivo (Mice and Medaka fish) models, we decided to investigate miR-211 and its target, the cytoskeleton associated protein Ezrin, to further understand IRDs pathophysiology and, hereafter, to target it to treat retinal diseases. These studies on Ezrin protein led to the treatment of autosomal dominant Retinitis Pigmentosa (adRP) vision loss and to reconstruction of its molecular network EGFR/Akt/TSC complex in the control of RPE health.

Downloads

Actions (login required)

Modifica documento