.BLASTED2 · Identification of molecular targets for the treatment of the skeletal phenotype in Lysosomal Storage Disorders
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2014-01-01 → 2017-12-31
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-CIG
Линиите свързват координатора с партньорите.
Накратко на български
Лизо좀ните нарушения пречат на хондроцитите да отделят колаген, което спира растежа на костите. Разбирането на този механизъм помага за подобряване на скелеталните проблеми при тези заболявания.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
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. The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs). We found that lysosomal dysfunction induces a constitutive lysosomal association and consequent activation of mTORC1 in chondrocytes, the cells devoted to bone elongation. mTORC1 hyperphosphorylates the protein UV radiation resistance–associated gene (UVRAG), reducing the activity of the associated Beclin 1–Vps34 complex and thereby inhibiting phosphoinositide production. Limiting phosphoinositide production leads to a blockage of the autophagy flux in LSD chondrocytes. As a consequence, LSD chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. In mouse models of LSD, normalization of mTORC1 signaling or stimulation of the Beclin 1–Vps34–UVRAG complex rescued the autophagy flux, restored collagen levels in cartilage, and ameliorated the bone phenotype. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest potential therapeutic approaches for the treatment of LSDs. This work was recently published (September 2017) in Journal of Clinical Investigation.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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.""
Оригинален текст от CORDIS (на английски).
Участници
- FONDAZIONE TELETHON ETS · ROMAКоординаторИталия
Връзки
Данни: CORDIS, © Европейски съюз