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QLK3-2000-00463
New anti-inflammatory natural products from medicinal plants using inducible transcription factors and their signalling pathways as molecular targets
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Quality of Life - 3. The Cell Factory
| Contract No: |
QLK3-2000-00463 |
| Project Type: |
RS (Research and Technological Development Project)
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| Start Date: |
01-01-2001 |
| Duration: |
36 months
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| Total Cost: |
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| EC Contribution: |
2 600 800 EUR |
| Scientific Officer: |
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Abstract
The consortium assembled here will contribute to the development of new
anti-inflammatory drugs for clinical use in the European Union and beyond by identifying
medicinal plant extracts with NF-kappaB inhibitory activity and/or inhibitory effects on targets
of the inflammatory cascade in periphearl and CNS tissues. These targets will include, for
example, IL-1beta (IL-1B), TNFalpha (TNFa), prostaglandin E2 (PGE2), and IL-6.
Subsequently, the compounds mediating this inhibitory effect will be isolated and their
structure elucidated. The consortium has the capacity to evaluate the extracts in a large
set of targets related to the transcriptional activation of gene products of relevance for
inflammatory, inflammatory, immunomodulatory and apoptotic activity. Select compounds
will be further studied in in vivo as well as in vitro systems and we expect that this research
will form the basis for pre-clinical and clinical development.
Objectives
Main objective of the Consortium's porposed research co-operation is the
identification of potent and specific modulators of NF-kappaB activation and of the signalling
pathways involved in the inflammatory response of the body.
These modulators may serve as lead compounds for developing new pharmaceuticals to
be used in the treatment of inflammatory diseases or conditions associated with an increased
activity of the transcription factor NF-kappaB. Among the illnesses to be treated with such new
pharmaceuticals are acute and chronic inflammatory diseases in peripheral tissue as well as
conditions like stroke and Alzheimer's Disease.
Another goal is to contribute to the evaluation of European and non-European medicinal
plants for use as novel therapeutics which constitutes an additional socio-economic value for the
EU and its people.
Description of the work
The research project combines up-to-date ethnobotanical knowledge with modern
molecular biology in order to identify potent inhibitors of the inducible transcription factor
NF-kappaB, cyclooxygenases 1 and 2, and receptors and/or their ligands (peripheral
TNFalpha, IL-6, PGE2, leukotriene B4 and IL-1B as well as PGE2, IL-6, TNFa
and nitric oxide (NO) in the CNS).
The consortium's project is divide into two lines of investigation:
- One line is looking at the mechanisms of inflammation in CNS tissues and the effects
of established inhibitors. in vivo and in vitro models for CNS inflammation, brain infarction,
brain trauma and Alzheimer's Disease will be established and transgenic rodents over-expressing
NF-kappaB-regulated inflammatory enzymes (iNOS, PKC-delta) berdNovel biological targets
involved in the kinase cascase related to NF-kappaB (especially novel RIP associated signalling
proteins) will be identified.
- The second line of research assesses plant extracts from >300 species for human
monocytes [inhibition of COX activity/PGE2 release and synthesis of the cytokines
IL-6, TNFa and IL-1B] and for their effect on apoptosis. Subsequent evaluation will lead to a
better understanding of the mechanism(s)of action. Pure natural products responsible for this
activity will be isolated and their structures elucidated in vitro and in vivo evaluation
of the most promising inhibitory compounds will combine both research streams: Compounds
exhibiting 'in vitro activity' will be studied for their anti-inflammatory effects in
the LPS-induced septic shock mouse model and the collagen-induced arthritis rodent model.
In parallel, we will assess pre-tested compounds for anti-inflammatory activity on the newly
identified targets in the CNS and in vivo models of stroke and Alzheimer's
Disease
Milestones
- Milestone 1: Prioritisation of the species and the selection of samples (WP1).
- Milestone 2: Identification of new targets in the RIP pathway (WP2) and the validating of th
role of NF-kB-dependent and independent inflammation in common brain diseases (WP3).
- Milestone 3: Selection of active plant samples based on the specificity and on the mechanism
of action.
- Milestone 4: Identification of novel inhibitors of NF-kB and of the inflammatory signalling
pathway.
- Milestone 5: Physiological and detailed biochemical characterisation of the novel
NF-kB inhibitors and the ones of the inflammatory signalling pathway (this will be the basis for
further drug development).
Deliverables
- Report on plants selected and active samples
- Database summarising all relevant information
- Extracts for further study
- Report of all relevant data including sequence data, bioinformatics analysis (RIP)
- Patent filing of novel RIP associated proteins
- Establishment of targets used in WPs 3 and 4
- Establishment of in vitro systems and Report on the role of NF-kB in animal/in vitro
(neuronal models)
- Establishment of in vivo systems for brain inflammation and report on the role of
NF-kB in these systems
- Establishment of transgenic animals
- Prioritised plant samples with known mechanism (NF-kB inhibitors)
- Patent filing of novel NF-kB inhibitors (standardised extracts) (susequently publications)
- Prioritised plant samples with known mechanism (anti-inflammatory)
- Patent filing of novel anti-inflammatories (standardised extracts)
- Pure compounds with anti-inflammatory and/or NF-kB inhibitory activity
- Report on the Results of WP6
- Patents on pure (novel) compounds covering biological activities (and structure)
(subsequently publications)
- Pure compounds with known mechanism (NF-kB cascade inhibitors)
- Patents on pure (novel) compounds covering biological activities (and structure)
(subsequently publications)
- A report describing the molecular targets of the inhibitors of the NF-kB cascase
- Pure compounds with known mechanism (anti-inflammatorics)
- Patents on pure (novel) compounds covering biological activities (and structure)
(subsequently publications)
- A report describing the molecular targets of the anti-infalmmatory compounds
from plants selected for this project
Contacts
Coordinator
Participant
