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Milano, Italy

The main objective of this research proposal is to identify and elaborate those characteristics of ENM that determine their biological hazard potential. This potential includes the ability of ENM to induce damage at the cellular, tissue, or organism levels by interacting with cellular structures leading to impairment of key cellular functions. These adverse effects may be mediated by ENM-induced alterations in gene expression and translation, but may involve also epigenetic transformation of genetic functions. We believe that it will be possible to create a set of biomarkers of ENM toxicity that are relevant in assessing and predicting the safety and toxicity of ENM across species. The ENM-organism interaction is complex and depends, not simply on the composition of ENM core, but particularly on its physico-chemical properties. In fact, important physico-chemical properties are largely governed by their surface properties. All of these factors determine the binding of different biomolecules on the surface of the ENM, the formation of a corona around the ENM core. Thus, any positive or negative biological effect of ENM in organisms may be dynamically modulated by the bio-molecule corona associated with or substituted into the ENM surface rather than the ENM on its own. The bio-molecule corona of seemingly identical ENM cores may undergo dynamic changes during their passage through different biological compartments; in other words, their biological effects are governed by this complex surface chemistry. We propose that understanding the fundamental characteristics of ENM underpinning their biological effects will provide a sound foundation with which to classify ENM according to their safety. Therefore, the overarching objective of this research is to provide a means to develop a safety classification of ENM based on an understanding of their interactions with living organisms at the molecular, cellular, and organism levels based on their material characteristics.


Grant
Agency: Cordis | Branch: H2020 | Program: ERC-ADG | Phase: ERC-ADG-2014 | Award Amount: 2.24M | Year: 2016

Membrane trafficking is fundamental for homeostasis of the internal membrane system and transport to and from the extracellular medium. Although we have gained detailed knowledge on the molecular organization of membrane trafficking machineries a global view of its function and regulation is lacking. To date membrane trafficking is often regarded as a constitutive process with a high degree of functional redundancy. However, the fact that mutations of single trafficking genes with ubiquitous expression give rise to tissue-specific human diseases and discrete sets of trafficking genes have differential effects on tissue development challenge this view. Here, using a combination of state-of the-art technologies, we will apply a systems biology approach in specialized cell types to establish a physiological and functional spatiotemporal map of membrane trafficking genes and proteins (membrane trafficking modules; MTMs). To this end we have curated a list of 1,187 genes representing ER, Golgi, Endosomes and Lysosomes (EGEL) around which we develop independent but interconnected approaches: (i) RNA-seq and antibody microarrays to identify co-regulated MTMs; (ii) high-content siRNA screening to define functional MTMs; (iii) epistatic functional analysis between EGEL genes and five membrane trafficking disease genes (TRAPPC2 in chondrocytes, Sec23A in osteoblasts, OCRL and CLCN5 in proximal tubular epithelial kidney cells, and VAPB in neuronal cells); and (iv) studies of protein-protein interactions to generate functional and physical networks centered on the disease genes. SYSMET will generate a unique resource by defining the impact and interplay of the different regulatory layers of the entire membrane trafficking system with important implications for human health.


Patent
Fondazione Telethon | Date: 2015-07-29

The invention refers to TFEB related molecules, as variants, mutants, truncated proteins, chimeras etc. that are constitutively localized in the nucleus of a eukaryote cell. Such molecules have a therapeutic applicability in all of disorders that need of an induction of the cell authophagic/lysosomal system, as lysosomal storage disorders, neurodegenerative diseases, hepatic diseases, muscle diseases and metabolic diseases.


Patent
Fondazione Telethon | Date: 2015-11-12

The invention provides for nucleotide sequences encoding for a chimeric sulfatase, viral vectors expressing such sequences for gene therapy and pharmaceutical uses of the chimeric expressed protein. The invention is particularly applied in the therapy of mucopolysaccharidosis, preferably type IIIA.


Patent
Fondazione Telethon | Date: 2014-07-15

A gene vector comprising a miRNA sequence target.

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