Objective
The overall objective of the project is to determine the role of in vitro systems as an alternative experimental approach to characterise the mode of action and molecular effects of neurotoxic metals of major environmental importance.
For these studies, lead, mercury, manganese and aluminium have been selected given a large body of clinical
evidence indicating their ability to induce neurological disorders in humans. The detrimental effects of these
metals in the mammalian nervous system are also documented by a number of conventional whole-animal
investigations.
A comprehensive approach is used integrating cytotoxicity assays and mechanistic studies to identify molecular
targets and critical end-points in neural cells exposed to metals in vitro. The project includes a series of
analytical and toxicokinetic studies as well as physiological validation assays using an experimental
in vitro/ex vitro design. Neutron activation analysis, radiotracers and gel filtration techniques are used to
quantitate trace metal levels in cultured cells and to examine the role of variables (i.e. metal uptake processes,
intracellular distribution, metabolism and binding to biomolecules) as factors determining the effective metal
concentration in exposed cells. Dose/effect relationships for metal interactions with cellular targets including
neurotransmitter receptors, second messenger systems
(phosphoinositide/protein kinase C, calcium signals, cyclic
nucleotides and nitric oxide pathway), gene expression, cytoskeleton, and physiological parameters of cellular
homeostasis (i.e. pH, membrane potential) are investigated. The systems used include primary cultures of cortical and cerebellar neurons, astrocytes and cell lines of neural
origin, namely rat PC12 cells and human SH-SY5Y neuroblastoma cells. Experiments are also carried out in living animals (rats) treated with lead, mercury, manganese or aluminium
to determine whether the effects that are observed in vitro after direct application of metals to cell cultures are
replicable and physiologically relevant under in vivo conditions. Parameters of cell signalling, cytoskeletal
proteins, gene expression and changes in susceptibility to cytotoxic insult are investigated in neural cells isolated
from fetal or neonatal rat brain after metal exposure of mothers throughout pregnancy.
Additional studies are intended to establish whether biochemical parameters which are measurable in peripheral
blood cells from animals chronically exposed to metals can be used as surrogate markers of neurotoxicity. In
these experiments, receptors and cell signalling components analogous to those affected by metals in the brain
are examined in blood lymphocytes and platelets from the same animal after treatment with toxic doses of lead
or mercury.
Expected achievements
Validation of mechanistic in vitro assays and cell culture systems as an alternative approach to whole animal
experiments in the area of metal neurotoxicology.
Development of advanced in vitro testing methods applicable to neuroscience and environmental toxicology
research for evaluating aspects of chemically-induced nervous system damage and repair such as
neurodegeneration, neuroprotection, neurotrophic events and developmental neurotoxicity.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- natural sciences biological sciences cell biology cell signaling
- natural sciences chemical sciences inorganic chemistry transition metals
- medical and health sciences basic medicine neurology
- medical and health sciences basic medicine physiology homeostasis
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
27028 SAN MARTINO SICCOMARIO
Italy
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.