Role of lysosomal processes in skeletal development and diseases, and identification of therapeutic approaches for the treatment of skeletal manifestation in Lysosomal Storage Disorders

Skeletal development is a coordinated process that in humans begins during embryogenesis and terminates at puberty. Skeletal elements are composed of two distinct tissues, cartilage and bone, and by three distinct cell types, chondrocytes, osteoblasts and osteoclasts. Several human genetic disorders are associated with defective skeletogenesis. Clinical studies indicate that 10% of all genes associated with skeletal disorders encode lysosomal proteins. The resulting disorders are known as lysosomal storage disorders (LSDs) whose incidence is about 1 in 5,000 - 10,000 births. Despite this, the mechanisms by which lysosomal dysfunction affects skeletal development and function are still unknown, and the efficacy of current therapies on the skeletal system are limited. The goal of this lab group is 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. We propose an unbiased approach to identify the differential responses of wild type and LSD cells to the molecules that regulate skeletogenesis. In addition, we plan to identify which factors secreted during skeletogenesis regulate lysosomal and autophagic functions. Finally, in vivo mouse models and pharmacological approaches can be used to test how modulating selected signaling pathways can be exploited to treat skeletal defects caused by lysosomal dysfunction. The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from July 2016 until last budget year, calculated based on the size of the research group.