INFORMAZIONI SU
CUTTINI Emma
 |
Supervisore:Dr.ssa Dardis Investigation of the mechanisms involved in the phenotypic diversity of Gaucher Disease and their potential role as therapeutic targets |
| Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder due to the deficit of the lysosomal enzyme β-glucocerebrosidase (GCase), encoded by the GBA1 gene. The enzyme deficiency leads to the accumulation of glucosylceramide and its deacylated derivate glucosylsphingosine (Lyso-Gb1) in the lysosomes, mainly in cells of the monocyte-macrophage lineage. The disease has been classified into three distinct clinical phenotypes, based on the presence and progression rate of neurological symptoms, being the non-neurological phenotype, GD type 1 the most frequent one. Two therapeutic approaches are currently approved for the treatment of the non-neurological manifestations of GD, namely, enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). However, the age of disease onset, clinical manifestations and therapy responsiveness are extremely heterogeneous among patients presenting the same clinical phenotype. Over 500 GBA1 pathogenic variants have been identified, but they can only partially explain GD phenotypic variability, as diversity has been recognized even among homozygous twins. This strongly suggests that GD is a complex disorder where genetic and non-genetic modifiers play a significant role in determining the disease course. Therefore, this project aims to explore these mechanisms and their potential role as therapeutic targets through a multi-omic approach, including transcriptomic and metabolomic analysis. The analyses will be performed on patient-derived monocytes, which will be differentiated in vitro into macrophages. The differentially regulated pathways between patients and controls will be validated and further explored using established GD in vitro models. In addition, the data will be exploited by the Recon4IMD project (Home | Recon4IMD), which aims to develop an AI-based personalised medicine approach for the diagnosis and management of inherited metabolic disorders. |
|