Molecular mechanisms affecting HDL functions and contributing to CAD risk

Información del proyecto

Identificador del acuerdo de subvención: BMH4983699

Proyecto cerrado

Fecha de inicio 1 Mayo 1998

Fecha de finalización 30 Abril 2001

Financiado con arreglo a

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

Coste total

Sin datos

Aportación de la UE

Sin datos

Coordinado por

FOUNDATION OF RESEARCH AND TECHNOLOGY - HELLAS
Greece

Objetivo

Objectives
1) To predict by computer modelling functionally relevant domains of apoA-I and apoA-II. 2) To utilise existing and generate new mutant forms of apoA-I and apoA-II that will be used to study the functions of these proteins. 3) To map the domains and residues of apoA-I and apoA-II involved in binding to the scavenger SR-BI type receptor or other cell receptors. 4) To map the domains and residues of apoA-I required for binding to lipids and activation of LCAT efflux of cholesterol from cells as well as the domains of apoA-II required for displacement of apoA-I from the surface of HDL. 5) To establish by transgenic methodologies how mutations that alter specific functions in vitro affect the functions or the concentrations of HDL in vivo and their impact on the development of atherosclerosis. 6) To generate and utilise commercially apoA-I and apoA-II derivatives of pharmacological importance for treatment or prevention of cardiovascular and other diseases.

Brief description
Epidemiological and genetic data combined with recent transgenic experiments suggest that increased apoA-I and HDL levels protect from atherosclerosis. In contrast, low HDL levels predispose to coronary artery disease (CAD), a leading cause of mortality world-wide. Existing knowledge suggests that the protective functions of HDL are mediated by apoA-I whereas apoA-II antagonises the functions of apoA-I. The partners will use interdisciplinary approaches and state-of-the-art structural molecular and biochemical methodologies and their complementary expertise to elucidate the functions of apoA-I and apoA-II in vitro and in vivo.
Computer modelling of apoA-I and apoA-II domains and existing functional information will be utilised to generate new variant forms of apoA-I and apoA-II. Existing and new mutants of apoA-I and apoA-II forms will be purified on a large scale and the proteins will be utilised for functional analysis in vitro. These analyses will aim at mapping of the functionally relevant domains of apoA-I and apoA-II which are involved in high affinity binding to cell receptors (high affinity binding site on HepG2 cells and SR-BI), binding to lipids and activation of LCAT, efflux of cholesterol from cells.
Transgenic mouse models will also be utilised for functional analyses of apoA-I and apoA-II in vivo. This will involve generation of transgenic mice expressing selected variant forms of apoA-I and apoA-II and analysis of the in vivo functions of the mutant proteins including their capacity to predispose or protect from atherosclerosis.
Commercial exploitation of apoA-I and apoA-II derivatives will involve utilisation of apoA-I and apoA-II derivatives which have improved biological functions as lead compounds to develop drugs to protect from cardiovascular disease by the industrial partner Glaxo Welcome.
Successful completion of the proposed work is expected to yield a wealth of information on the biological mechanisms associated with the functions of apoA-I, apoA-II, HDL and their receptors which are relevant to the protection from CAD. This information will open new avenues which may lead to the development of new pharmaceuticals for the prevention and/or treatment of cardiovascular disease.

Keywords.
Apolipoprotein A-I, apolipoprotein A-II, HDL, CAD, A-I receptor, transgenic mice, scavenger SR-B1 receptor, reverse cholesterol transport, signal transduction, LCAT activation.

Ámbito científico (EuroSciVoc)

• ciencias médicas y de la salud › medicina básica › farmacología y farmacia › medicamento
• ciencias médicas y de la salud › medicina clínica › cardiología › enfermedad cardiovascular › arteriosclerosis
• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › lípidos
• ciencias naturales › matemáticas › matemáticas puras › análisis matemático › análisis funcional

Programa(s)

• FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Tema(s)

• 4.3.1 - Pathophysiology and basic mechanisms

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

CSC - Cost-sharing contracts

Coordinador

FOUNDATION OF RESEARCH AND TECHNOLOGY - HELLAS

• Aportación de la UE: Sin datos
• Dirección: Vassilika Vouton ; 71110 IRAKLION ; Grecia
• Coste total: Sin datos

Participantes (5)

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

Francia

• Aportación de la UE: Sin datos
• Dirección: Place du Docteur Baylac ADR 4 - Midi-Pyrénées Hô ; 31059 TOULOUSE
• Coste total: Sin datos

Laboratoires Glaxo Wellcome S.A.S.

Francia

• Aportación de la UE: Sin datos
• Dirección: 25,Avenue du Québec ; 75764 Paris
• Coste total: Sin datos

Universiteit Gent

Bélgica

• Aportación de la UE: Sin datos
• Dirección: 13,Hospitaalstraat ; 9000 Gent
• Coste total: Sin datos

Université Pierre et Marie Curie - Paris VI

Francia

• Aportación de la UE: Sin datos
• Dirección: 15,Rue de l'Ecole de Médecine ; 75006 Paris
• Coste total: Sin datos

Westfdlische Wilhelms - Universitdt Münster

Alemania

• Aportación de la UE: Sin datos
• Dirección: 33,Albert Schweitzer Strasse ; 48149 Münster
• Coste total: Sin datos