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Periodic Report Summary 1 - .BLASTED2 (Identification of molecular targets for the treatment of the skeletal phenotype in Lysosomal Storage Disorders)

Lysosomes are the major catabolic organelles within the cell, being central for degradation and recycling of macromolecules delivered by endocytosis, phagocytosis, and autophagy. More recently, the lysosomes emerged as key regulators of the Mechanistic target of Rapamycin kinase complex 1 (mTORC1) activity in response to nutrients. However, to date the physiological relevance of this lysosomal signaling activity is still largely unexplored. We are currently investigating the role of lysosomal and autophagy signaling in the pathogenesis of lysosomal storage disorders. In particular with the support of BLASTED2 funding we are investigating the role and the regulators of autophagy and lysosomal pathways during bone growth in order to identify new approaches for the treatment of skeletal phenotype in Lysosomal Storage disorders (LSD).
We demonstrated that autophagy and lysosomal function is important to regulate collagen levels in the developing bones. Chondrocytes lacking autophagy or affected by lysosomal storage fail to produce the proper amount of collagen during bone growth. We also demonstrated that post-natal induction of chondrocyte autophagy is mediated by the growth factor FGF18 through FGFR4 and JNK-dependent activation of the autophagy initiation complex VPS34–beclin-1. These data demonstrate that autophagy is a developmentally regulated process necessary for bone growth, and identify FGF signalling as a crucial regulator of autophagy in chondrocytes. In addition have found that chondrocytes and mesenchimal cells isolated from LSD patients and mouse models display persistent mTORC1 association to lysosomes and enhanced signaling of mTORC1 in response to nutrients. Genetic and pharmacological restoration of mTORC1 activity rescues autophagosome/lysosome fusion and autophagy substrate accumulation in LSD chondrocytes. These data demonstrate the relevance of lysosome as regulator of mTORC1 signaling and suggest a role for mTORC1 in the pathogenesis of lysosomal storage disorders.
In addition, the support of BLASTED2 grant was also instrumental for the establishment and growth of Dr. Settembre’s group in the host institute. The group is now composed of 2 PhD student, 3 post docs and 2 technicians while at the time of BLASTED2 application the group was composed only of 1PhD student and 1 technician. The data generated in Dr. Settembre in the last two years, also thanks to BLASTED2 support, led to the award of different grants and to the publication of a scientific article in Nature magazine in which Dr. Settembre is listed as senior author. These successes gave also the possibility to Dr. Settembre to be appointed as tenure track assistant professor (RTD-B) in Genetics at the Federico II University of Naples. This position will very likely allows Dr. Settembre to be promoted as Associate Professor within the next two years, hence to obtain a stable permanent position.

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Life Sciences