RICERCA ITALIANA     

Mechanisms of signal transduction and synaptic function: Development of molecular, cellular, and animal models.

Istituto Europeo di Oncologia

Abstract

Synapses are highly organized cellular compartments. Within synapses, a complex network of physiological relationships determines structural and functional modifications that determine the mode of action of neuronal circuitry. Important progress in the characterization of the molecular mechanisms involved in the synaptic function has been achieved in the past years. This research proposal lies within the mainstream of this characterization work. We propose to study proteins that play a fundamental role in synaptic function from substantially complementary points of view. Some of these proteins, such as the Epsins and Eps15, constitute part of the molecular machinery involved in synaptic vescicle recycling. Other targets in this study are certain members of the protein kinase family, such as Src, CDK5, ACK, ErbB, and their interactors and regulators, that have a documented or an expected role in different aspects of synaptic function. Finally, we plan to study proteins, such as the catenins, which perform in cellular adhesion and in the regulation of the cytoskeleton. The strength of our approach resides in the coherent aggregation of groups with different scientific background, from X-ray crystallography to mouse genetics, for the characterization of the above-mentioned factors. Understanding the mechanisms that regulate the interactions of these factors with other macomolecular complexes and specific organelles is of utmost importance for the comprehension of neuronal cell>>>

Principal Investigator

ANDREA MUSACCHIO, ISTITUTO EUROPEO DI ONCOLOGIA

Research Goal

The emerging data suggest that synapses can be considered as autonomous compartments in which diverse signaling pathways are activated resulting in structural and functional changes in neuronal circuits. Thus, understanding how synaptic functions are regulated by either ubiquitous or brain-specific signaling molecules is a fundamental undertaking with far-reaching implications from molecular through behavioral neurobiology. Moreover, a better understanding of such synaptic signaling mechanisms may reveal novel approaches for preventing and treating an array of neurodegenerative conditions that are initiated by perturbed synaptic homeostasis.

This network aims at the detailed elucidation of the structure-function relationship of selected synaptic molecules that are critically involved in the regulation of fundamental synaptic functions. This will be accomplished by their functional and structural investigation and by the generation and phenotypic characterization of genetically-modified cellular and animal models which will allow to address questions of higher complexity in the context of synaptic transmission and synaptic plasticity. The rationale and the feasibility of our proposal relies on the fact that molecules which fulfill crucial signaling functions in synaptic compartments are available for structural/biochemical and functional studies within our network.

The proposed research has four overall scientific objectives:

A) to>>>

Timescale

36 months