Molecular and Cellular Neuroscience

Guido Cavaletti
Guido Cavaletti Email: molecular@neuromi.it
The research activity of this area involves several aspects of basic neuroscience, with a focus on the translational aspects of the studies in both the central and the peripheral nervous system. Advanced in vitro, ex vivo and in vivo models have been specifically developed to investigate the processes leading to the normal development, maturation and ageing of the nervous system, as well as the detection of pathogenetic mechanisms at the basis of neurological and psychiatric diseases. Multidisciplinarity is an area key word, since basic researchers work in strict collaboration with neurologists, neurosurgeons, psychiatrists and clinical researchers from related fields.
  1. Neurodegeneration, stroke and epilepsy
    In the field of neurodegeneration, research on oligomeric Abeta and glutamate toxicity, as well as Pin1 isomerase activity are coupled with experimental therapeutic attempts in fibroblasts from Alzheimer’s disease patients and neuroblastoma cells. Voltage-gated currents and postsynaptic potentials, functional alterations of the blood-brain barrier (BBB) are also investigated. The role of Parkinson’s disease-related toxins, genetic alterations and neuroprotective agents on lysosomal catabolic pathways for alpha-synuclein are also investigated, as well as cholinergic and hypocretinergic regulation of synaptic circuits in the prefrontal cortex. Cerebrotendinous xanthomatosis and Spastic paraplegia type 5 are used as models of neurodegeneration due to defective cholesterol metabolism. Metalloprotease ADAM10 is investigated as a new potential target in the Huntington’s disease brain. Prion Protein (PrPc) folding in neuronal membranes and lipid rafts constituents are also established research topics, linked with investigations on air pollution relevance in protein misfolding and neurodegenerative diseases. Recently, the studies in the advanced field of induced pluripotent stem (iPS)-derived neurons from fibroblasts have also been started.
    Experimental stroke models in vivo have been developed in order to reproduce transient focal cerebral ischemia and intracerebral hemorrhage, with the final aims to determine the pathogenesis of neuronal damage and to test advanced experimental therapies, including collateral therapeutics and selective cerebral spinal fluid hypothermia.
    Search for new candidate genes involved in epileptic phenotypes and autism through next generation and microarray techniques and identification, in vitro and in vivo characterization of new mutations in known genes involved in epilepsies are performed by genetists in collaboration with neurologists, neurophysiologists and child neuropsychiatrist. The effects of newly developed peptidic and non peptidic drugs are studied in the in vivo model of pilocarpine-induced epilepsy.
  2. Neuro-oncology and pain
    Neuro-oncology is a field of close contact between basic researchers, neurosurgeons, genetists and pathologists, addressing the issue of the pathogenesis and treatment of brain cancer. Innovative treatments based on the use of frontline therapy using synchrotron radiation and photoactivation of suitable drugs (e.g. high z-number compounds) are under investigation in collaboration with the European synchrotron radiation source in Grenoble.
    Together with radiotherapy, systemic chemotherapy is one of the cornerstones of cancer treatment, but neurotoxicity is currently the major dose limiting side effect after hematological toxicity. Cellular and animal models of chemotherapy-induced peripheral neurotoxicity have been originally developed and characterized by researchers of this area, and they represent the international “gold-standard” in this fields.
    Neuropathic pain, a challenging clinical problem in affected patients, is investigated in vitro and in vivo at the behavioral, pharmacological, pathological and neurophysiological levels and innovative therapeutic approaches are attempted, also in collaboration with leading International pharmacological companies.
  3. Neuro-inflammation, cellular transplants and regeneration
    The possibility to allow effective neuro-regeneration and immune-modulation using mesenchymal stem cells (MSCs) is tested in well-characterized cellular and animal models. The paracrine actions of MSCs on different cell populations of the central nervous system are investigated in in vitro cellular models. Moreover, the critical aspect of genetic stability of MSCs is investigated through their genomic-epigenomic profiling and non-nervous adult cell transplants are explored to treat neurological complications of systemic diseases (e.g. diabetes).
    Multiple sclerosis, and more broadly the field of neuro-inflammatory diseases of the central and peripheral nervous system, is investigated in close collaboration with neurologists and experts in basic immunology at the cellular and animal levels. Integrated chemical-biology approach to the study of Toll-Like Receptor 4 (TLR4) activation and signaling, implication of TLR4 in innate immunity, inflammation and neuro-inflammation, development of small molecule TLR4 modulators as new therapeutics for neuro-inflammatory and neurodegenerative diseases are main topics in this field.
  4. Development and brain functioning
    The cellular and molecular mechanisms underlying synaptic formation and function and their roles in the developmental of neuro-behavioural disorders, such as autism and schizophrenia are carried out in collaboration by pharmacologists and adult/child psychiatrist, while another research line is focused on the genetic study of rare malformative syndromes associated to mental retardation.
    Several transduction and intracellular signaling systems are explored in neurons and glial cells, including small G-proteins, Ras and Ral activators, Map kinases, deubiquitinating enzyme USP8, mitochondrial structures and their modulation as well as the use of trophic factors (e.g. NGF, NGF-like molecules) for therapeutic aims is investigated also profiting from system biology methods. Functional and pharmacological studies of ion channels are applied to genetic diseases.
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