Development and maintenance of the central noradrenergic phenotype

Información del proyecto

Identificador del acuerdo de subvención: BIO4980112

Proyecto cerrado

Fecha de inicio 1 Septiembre 1998

Fecha de finalización 28 Febrero 2001

Financiado con arreglo a

• Specific research, technological development and demonstration programme in the field of biotechnology, 1994-1998

Coste total

Sin datos

Aportación de la UE

Sin datos

Coordinado por

MAX-PLANCK-GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.
Germany

Objetivo

The locus coeruleus (LC) is the main noradrenergic centre of the brain and the most widely projecting central nervous system nucleus known. The LC has been proposed to play a role in the plasticity of the visual cortex (1), in attention and vigilance (2), as well as in the control of mood (3), memory acquisition (4) and selective attention (5). The LC is a major target of degenerative disorders such as Parkinson and Alzheimer disease and Down's syndrome (6-8). Finally, the LC plays a key role in triggering the opiate withdrawal syndrome (9) and is a prime model for studying the molecular basis of opiate habituation and deshabituation (10).
Whereas many studies have been devoted to the anatomy, pharmacology and electrophysiology of the LC, little is known of its ontogeny and cellular biology. The analysis of these aspects could provide important insights in its functioning and maintenance as well as inspire therapeutic strategies. Indeed, signals regulating the development of particular neuronal lineages are known to be important for the maintenance and plasticity of the differentiated phenotype under physiological and pathological conditions in the adult. For instance, neurotrophic factors that are survival factors for several classes of embryonic neurons also prevent lesion-induced degeneration of the same neurons in the adult. This proposal focusses on the molecular mechanisms involved in the determination of LC neurons and on their trophic dependency throughout embryonic and postnatal life.
The main immediate objectives are:
1. to reappraise the normal development of the LC (and noradrenergic centers A1 and A2) in the light of novel markers and concepts of neural tube regionalization;
2. to explore the transcriptional control of LC development and maintenance, in particular by the homoeodomain proteins Phox2a and Phox2b;
3. to study the requirements for survival and maintenance of the noradrenergic phenotype in vivo and in cultures of differentiated LC neurons, in particular the neurotrophic dependencies of LC neurons;
4. to establish conditions that would allow the generation of central noradrenergic neurons in vivo and in-vitro.
By taking a multi-disciplinary approach, combining studies on cultured cells with in vivo studies in both chick and mouse and exploiting the experimental advantages offered by each species, we ultimately hope to understand the sequence of events involved in the generation and maintenance of central noradrenergic neurons. We expect that our studies will lead to a better understanding of several diseases and dysfunctions of the LC and ultimately to the development of new therapeutic strategies for neuroprotection and for the prevention of opiate habituation and withdrawal syndromes. For instance, the understanding of the signalling involved in the generation of noradrenergic neurons may lead to transgenic models of specific noradrenergic deficiencies and to the development of engineered progenitor cell lines that may be of therapeutic interest for neurodegenerative diseases involving the LC.
Thus, our proposal complies with the objectives of the work programme in that the cellular and molecular mechanisms of LC development are investigated to provide a basis for the understanding of multiple dysfunctions of this important neural centre.

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › neurobiología
• ciencias médicas y de la salud › medicina básica › neurología › demencia › alzheimer
• ciencias médicas y de la salud › medicina básica › anatomía y morfología
• ciencias médicas y de la salud › medicina básica › neurología › parkinson
• ciencias médicas y de la salud › medicina básica › farmacología y farmacia

Programa(s)

• FP4-BIOTECH 2 - Specific research, technological development and demonstration programme in the field of biotechnology, 1994-1998

Tema(s)

• 0401 - Development of the nervous system

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

CSC - Cost-sharing contracts

Coordinador

MAX-PLANCK-GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.

• Aportación de la UE: Sin datos
• Dirección: Deutschordenstrasse 46 ; 60528 FRANKFURT AM-MAIN ; Alemania
• Coste total: Sin datos

Participantes (4)

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE

Francia

• Aportación de la UE: Sin datos
• Dirección: 31,Campus de Luminy ; 13288 MARSEILLE
• Coste total: Sin datos

Consejo Superior de Investigaciones Cientificas

España

• Aportación de la UE: Sin datos
• Dirección: 37,Avenida Doctor Arce ; 28002 Madrid
• Coste total: Sin datos

KAROLINSKA INSTITUTE

Suecia

• Aportación de la UE: Sin datos
• Dirección: 12 A,Doktorsringen 12 A ; 171 77 STOCKHOLM
• Coste total: Sin datos

Universidad de Murcia

España

• Aportación de la UE: Sin datos
• Dirección: Campus de Espinardo ; 30010 Murcia
• Coste total: Sin datos