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The
Foundation's work
Supporting
research programmes
June
2007
Programme
title: Etude par imagerie neurofonctionnelle des bases neurales des troubles
autistiques dans le syndrome X-fragile.
Programme
director: Dr Dr Monica Zilbovicius (Unité INSERM-CEA 797
" Neuroimagerie et Psychiatrie ", Service Hospitalier Fréderic
Joliot, ORSAY)
Summary :
Amount
of funding: 20 000 euros.
December
2006
Programme
title: Targeting the pro-apoptotic protein Bid to prevent neuronal cell
death after cerebral ischemia
Programme
director: Dr Abdel AOUACHERIA (Institute of Biology and Chemistry
of Proteins, Lyon)
Summary : Sustained cell death causes the loss of neurons and neurological
deficits following stroke or neurodegenerative diseases. Bid is a key
pro-apoptotic member of the Bcl-2 family which acts upstream in the control
of the apoptotic program, leading to neuronal cell death in numerous experimental
models relevant to neurological disorders. In particular, Bid is a critical
mediator of ischemic cell death within the central nervous system, as
shown by investigations in Bid-/- knock out cells and animals. Bid therefore
constitutes an attractive target for strategies directed towards the development
of neuroprotective therapeutics. The overall aim of the project is the
discovery and development of small-molecule inhibitors targeted at Bid
and capable of inhibiting Bid-induced cell death in vitro and in vivo.
Upon apoptosis induction, Bid is activated by proteolytic cleavage, moves
to mitochondria and permeabilizes the outer mitochondrial membrane, thereby
promoting cytochrome c release into the cytosol and cell death. Using
the NMR three-dimensional solution structure of Bid, we recently employed
a docking-based computer approach to screen a virtual database of about
35,000 organic compounds to identify potential Bid small-molecule inhibitors.
Thirty molecules were predicted to bind to two hydrophobic clefts on the
surface of the Bid protein. We now wish to test experimentally which of
these "hits" bind to Bid using NMR methods. Thereafter, we will
determine the ability of the candidate drugs to inhibit Bid-induced apoptosis
activation in isolated mitochondria and in neuronal cell cultures, through
the monitoring of Bid cleavage, caspase-3 activation and cytochrome c
release. The ability of the potential inhibitors to reduce cell death
after glutamate-mediated excitoxicity or oxygen-glucose deprivation will
be measured. Biochemical studies on lipid monolayers and liposomes will
be performed to determine whether the chemical compounds can inhibit truncated
Bid (tBid) membrane integration or pore formation. Next, therapeutical
and biopharmaceutical evaluation of the promising molecules will be performed
in vivo. Protective effects will be assayed in murine acute models of
neuronal cell death (i.e. after middle cerebral artery occlusion or brain
trauma).
Nonpeptide chemical inhibitors of Bid (and of its active form tBid) will
represent invaluable tools for elucidating the role of this death protein
in neurodegenerative disorders. Moreover, small-molecule compounds selectively
targeting Bid could serve as lead compounds for future drug development
in the treatment of cerebrovascular accidents (as pharmacologic adjuncts
to current anti-thrombolytic therapy), as well as in various neurodegenerative
brain disease. It is likely that blocking apoptosis signals at the mitochondrial
level by inhibiting the function of Bid would be a far more effective
therapeutic approach compared to other strategies acting downstream of
mitochondrial damage
Keywords:
Bid, stroke, ischemia, cell death, apoptosis, mitochondria, drug discovery,
three-dimensional structure
Amount
of funding: 15000 euros
*****************
Programme
title: Quantification et localisation des plaques amyloïdes cérébrales
dans la maladie d'Alzheimer par Tomographie par Emission de Positons avec
le [18F]FDDNP
Programme
director: Pr Vincent Camus (Unité INSERM U619, TOURS)
Summary :
Amount
of funding: 15000 euros
*****************
Programme
title: Mirror
Neuron System in autistic pathology.
Programme
director:
Dr
Joëlle Martineau (Unité
INSERM U619, TOURS)
Summary
: This project is the continuation of two Regional Hospital Clinical Research
Programs obtained in 2001 and 2003 which were related respectively to
the visual perception of the movement and to the implication of the canonical
neurons in the visuo-guided grasping in young autistic adults compared
with healthy adult subjects.
Autism is a pervasive developmental disorder associated with considerable
impairments. In this pathology, the deficits of communication and socialization
are prevalent. These deficits could be related to difficulties in recognizing
emotional facial expressions. In this project, we consider the assumption
of a deficit of the "system of mirror neurons" in this pathology.
The mirror neuron system is a neural network (including the pre-motor
cortex, the superior temporal sulcus and the parietal cortex) and generates
internal representations of actions performed either by the subject or
by another person. It has been hypothesized to provide the neural basis
of "mind reading" and empathy and may play an important role
in autistic social deficits.
The presence of anomalies of the mirror neuron activations in the autistic
pathology is an assumption on which we have worked for several years.
Our first research carried out with functional MRI explored observation
and execution of biological movements. The results showed particularities
of activation in the cerebral areas composing this system of mirror neurons
during observation of biological movement in autistic patients.
The study of cerebral reactivity during anticipation to adjust the movement
of catch and grasp by the hand with or without eye gaze is being currently
carried out in young adults with autism in fMRI. These explorations will
allow the description of neuronal systems (system of canonical neurons)
specifically activated during goal-directed actions, systems therefore
implied in the visuo-motor processes in healthy adults and in autistic
patients. The first results show activations of the pre-motor cortex and
intraparietal sulcus in control subjects. All autistic subjects have already
been recorded.
The third part of the project, carried out in functional MRI (fMRI) will
explore activation of mirror neurons during comprehension of other people's
emotions. In parallel, an "eye-tracking" study performed in
both adults and children (healthy and with autism) will supplement the
functional imagery data and will aim at identifying behavioural profiles
for perception of faces expressing an emotion.
The behavioural study performed in children (healthy and with autistic
syndrome) and in adults (healthy and with autistic syndrome) is completed.
The study in imagery, only carried out in adults is also completed
The purpose of our request is the temporary recruitment of an engineer
who would enable us to process the results (in eye-tracking and fMRI),
to interpret them and to publish them more quickly. The results obtained
will be used to develop therapeutic and educational projects adapted to
autism in particular to rehabilitate the functions of perception and recognition
of facial expressions.
Amount
of funding: 15000 euros
January
2006
Programme title: Pathological angiogenesis in temporal lobe epilepsy:
impact on haemodynamics and drug resistance.
Programme
director: Dr Mireille Lerner-Natoli
Summary : Epilepsy
is a common neurological disease which affects about 1% of the population.
The attacks are due to paroxystic activity of a group of neurones, the
attacks varying widely according to the number and locality of these neurones.
Many forms of epilepsy are successfully treated with anti-epileptic drugs,
but about a third are resistant to these treatments. When the attacks
are too debilitating the only solution is to remove the epileptic focus
surgically, if it is accessible. The majority of drug-resistant forms
have their focus in the temporal lobe and are characterised by complex
attacks with loss of consciousnessWe are a team of scientific researchers
and clinicians studying tissue from epileptic surgery to understand the
mechanisms of neuronal hyper-excitability and drug resistance. We have
recently observed significant reorganisation of nerve cells and also blood
vessels of the focus. The vascularisation of the focus and the adaptation
of blood flow to the neuronal activity are important because neurones
in seizure require an enormous amount of energy, while the blood flow
appears less functional between crises, the reason for which is still
unknown. Moreover, blood vessels in the brain are equipped with a barrier
that filters blood components preventing intoxication of neurones but
which under normal conditions allows drugs through. However, the vascular
reorganisation that we have observed suggests that the vascularisation
of epileptic foci is pathological, with numerous twisted vessels, and
proliferation of glial cells around the vessels which could prevent drugs
crossing the barrier.
We would now like to study this abnormal vascularisation in epilepsy by
quantifying its extent and correlating it with changes in blood flow and
expression of drug-filtering proteins. These experiments will be carried
out using functional imaging examinations and surgical specimens, thus
not requiring additional examinations for the patients. We need imaging
and analysis equipment to observe and quantify pathological vascularisation
of epileptic foci.
This project will extend our understanding of the mechanisms involved
in epilepsy and drug resistance, and should help identify new therapeutic
strategies.
Key words: Epilepsy, Vascularisation pathology, drug resistance.
Amount
of funding: 26,000 euros to purchase an image-acquisition camera for
microflourescence and Métamorphe image-analysis software
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