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Volume 2
     

Targeting heme-oxygenase-1 or downstream processes: A new therapeutic approach for treatment of inflammation (HO-1)

   
Project

QLK3-2001-00422

Cell factory area

3.1.2

EU Contribution

2,628,575 Euro

Duration

36 months

Type

RS

Starting date

01 December 2001

Keywords
antigen-specific immune responses
anti-inflammatory effectors
overexpression
up-regulation
ABSTRACT

Chronic inflammation processes play a key role in the pathogenesis of many diseases with high morbidity and mortality such as rheumatoid arthritis (320,000 cases in Europe), inflammatory bowel disease (800,000 cases), multiple sclerosis, acute and chronic transplant injury (18,000 transplantations per year). Because of their high prevalence and chronic course they are associated with rising health costs and decreased quality of life. Nevertheless, even if these diseases place a heavy social and economic burden on the resources, the number of safe and effective treatments is still limited. During the past decade, major contributions to the understanding of genetic, environmental, biochemical, molecular and cellular mechanisms regulating inflammation have been developed. More recently, a novel mechanism of cytoprotection and immunmodulation by overexpression of heme oxygenase-1 (HO-1) was discovered. The aim of the present project is to better understand the mechanisms of HO-1 action and to design novel drugs inducing HO-1 or its downstream mediators.

OBJECTIVES
  1. development of novel therapeutic compounds up-regulating HO-1 expression in vivo.
  2. generation of genetically engineered rodents and gene transfer vectors to study effects of HO-1 expression (or lack thereof) on inflammation.
  3. characterisation of signal transduction pathways used by HO-1 or its downstream products.
  4. identification of putative intracellular targets of HO-1 or its downstream products.
  5. study of the effects of HO-1 on pro/anti-inflammatory effector functions in vitro.
  6. study of the effects of HO-1 expression in in vivo models of inflammation.
  7. study of the effects of HO-1 expression on initiation, maintenance and defector phases of antigen-specific immune responses.
DESCRIPTION OF THE WORK

The project is based on seven work packages:

  • WP1 will focus on the rational design synthesis and screening of new peptides that up-regulate HO-1 activity. The activity will be proved in vitro and in vivo in different models.
  • WP2 will focus on the generation of HO-1 deficient mice, HO-1 transgenic mice under the control of different tissue specific promoters, adenoviral, retroviral and lentiviral vectors encoding HO-1. The tools will be supplied to the network laboratories.
  • WP3 will focus on the comparision of the effects of HO-1 up-regulation and carbon monoxide (CO) in animal models of inflammation.
  • WP4 will focus on the effects of HO-1 and CO on cell-cell interactions regulating immune responses, particularly the interaction between dendritic cells and T-cells.
  • WP5 will focus on the identification of putative intracellular targets of HO-1 and CO in monocytes/macrophages.
  • WP6 will focus on the characterisation of signal transduction pathways used by HO-1 and CO in endothelial cells.
  • WP7 reflects the co-ordination and management of the project.
DELIVERABLES
  1. identification of novel active peptides by rational design combined with in vitro/in vivo screening.
  2. production of sufficient amounts of selected peptides for testing in different in vivo models.
  3. HO-1 Transgenic and ko. rats/mice.
  4. different HO-1 encoding vectors.
  5. comparison of pharmacological and genetic overexpression of HO-1 in different in vivo models.
  6. comparision of overexpression of HO-1 and its downstream products.
  7. definition of gene expression profiles in HO-1 overexpressing endothelial cells and macrophages.
  8. identification of signaling pathways mediating HO-1 and CO effects.
CONSORTIUM
COORDINATOR
 
Hans-Dieter Volk
Institute Med. Immunol.
Charité. HUB
10098 Berlin, Germany
Tel: +49-30-45052 4062
Fax: +49-30-45052 4932
hans-dieter.volk@charite.de
 
PARTNERS
 
Stefan Tullius
Department Surgery
Charité, HUB
13353 Berlin, Germany
Tel: +49-30-45055 2000
Fax: +49-30-45052 4932
stefan.tullius@charite.de

Giorgos Kollias
Institute Immunology
Fleming Institute Athens
16672 Vari, Greece
Tel: +30-1 965 6507
Fax: +30-1 965 3934
giorgos_kollias@hol.gr

Giesa Tiegs
Exp./ClinicalPharmacol
University Erlangen
91054 Erlangen, Germany
Tel: +49-9131-85 22771
Fax: +49-9131-85 22774
gisa.tiegs@pharmakologie.uni-erlangen.de

Jerome Tiollier
Research/Development
Imtix-Sangstat
69280 Marcy l´Etoile, France
Tel: +33-437-281 671
Fax: +33-437-285 899
tiollier@sangstat.fr

C.G. Figdor
Department Immunol
University Nijmegen
6500 HB Nijmegen, The Netherlands
Tel: +31-2 4361 7600
Fax: +31-2 4354 0339
c.figdor@mailbox.kun.nl

Ignacio Anegon
Department Immunology
INSERM U437/ITERT
44093 Nantes, France
Tel: +33-2-4008 7415
ianegon@nantes.inserm.fr

Miguel Soares
Institute Gulbenkian de Cienca
University Lisboa
2780-156 Lisboa, Portugal
Tel: +351-21-4407 900
Fax: +351-21-4407 970
mpsoares@igc.gulbenkian.pt

Dean Willis
Department Immunol.
University College London
London WC1B 6BT, United Kingdom
Tel: +44-20-7679 3755
Fax: +44-20-7679 7298
dean.willis@ucl.ac.uk