Objective "Lysosomal storage disorders (LSDs) are inherited diseases characterized by progressive intracellular accumulation of undigested macromolecules due to lysosomal dysfunction. This results in a complex phenotype with broad pathological manifestations. Most LSDs are characterized by defective skeletogenesis. Despite this, the mechanisms by which lysosomal storage affects skeletal development and function is still unknown and the efficacy of current therapies on the skeletal system is limited. This project aims at identifying the molecular mechanisms that underlye the skeletal abnormalities in LSDs and to develop novel therapeutic strategies directed toward these defects. In recent years, the lysosome has emerged as a key signaling centre, which regulates and is in turn regulated by the activity of signaling molecules. By using the Mucopolysaccharidosis VII (MPSVII) and the Multiple Sulfatase Deficiency (MSD) mouse as models of LSD, we plan to characterize the consequences of lysosomal dysfunction on major signaling pathways involved in skeletogenesis, and to identify tools and pathways that prevent accumulation and/or promote clearance of storage in bone cells. Once identified, the molecular players in these signaling pathways are appealing therapeutic targets for the treatment of the skeletal phenotype in LSD.The enhancement of lysosomal function can promote “cellular clearance” in cells affected by lysosomal storage even without correcting the underlying genetic defect. Supported by strong preliminary data, we will use genetic and pharmacological manipulation of TFEB, the master transcription factor that regulates lysosomal biogenesis, as a tool to promote clearance and in turn rescue the skeletal abnormalities of LSDs. In summary, this project aims to identify the pathogenetic mechanisms underlying the skeletal manifestation of lysosomal storage disorders and to provide proof-of-principle that these skeletal features can be treated." Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2013-CIG - Marie-Curie Action: "Career Integration Grants" Call for proposal FP7-PEOPLE-2013-CIG See other projects for this call Funding Scheme MC-CIG - Support for training and career development of researcher (CIG) Coordinator FONDAZIONE TELETHON ETS EU contribution € 100 000,00 Address VIA VARESE 16/B 00185 Roma Italy See on map Region Centro (IT) Lazio Roma Activity type Research Organisations Administrative Contact Irene Mearelli (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
