CHEMBIONMR

Using chemical-biology to synthesis and study nuclear receptor proteins

 Coordinatore TECHNISCHE UNIVERSITEIT EINDHOVEN 

 Organization address address: DEN DOLECH 2
city: EINDHOVEN
postcode: 5612 AZ

contact info
Titolo: Mr.
Nome: J.M.R. (Rob)
Cognome: Debeij
Email: send email
Telefono: +31 40 2475135

 Nazionalità Coordinatore Netherlands [NL]
 Totale costo 183˙805 €
 EC contributo 183˙805 €
 Programma FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
 Code Call FP7-PEOPLE-2011-IEF
 Funding Scheme MC-IEF
 Anno di inizio 2012
 Periodo (anno-mese-giorno) 2012-04-01   -   2014-03-31

 Partecipanti

# participant  country  role  EC contrib. [€] 
1    TECHNISCHE UNIVERSITEIT EINDHOVEN

 Organization address address: DEN DOLECH 2
city: EINDHOVEN
postcode: 5612 AZ

contact info
Titolo: Mr.
Nome: J.M.R. (Rob)
Cognome: Debeij
Email: send email
Telefono: +31 40 2475135

NL (EINDHOVEN) coordinator 183˙805.80

Mappa


 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

breast    ptms    biological    tamoxifen    play    oestrogen    dependent    biophysical    site    probe    ligand    biology    phosphorylation    activation    function    nuclear    subsequent    therapies    cancer    functions    receptor    studying    synthesis    molecular    ptm    chembionmr    post    constructs    techniques    synthetic    molecules    worldwide    chemical    er    modifications    disease    forms    binding    diseases    chemistry    translational    drug    critical   

 Obiettivo del progetto (Objective)

'The rapidly growing field of Chemical Biology combines the power of synthetic chemistry with the spectrum of micro- and molecular biology techniques, thus important challenges in medicine can be addressed in revolutionary new ways. This innovative methodology allows problems associated with studying diseases and designing novel drug-like molecules to be tackled in a unique approach. A recent example is the combination of synthetic carbohydrate chemistry with parasite glycobiology that has led to a new candidate for a malaria vaccine. Besides infectious diseases, cancer is a major cause of death worldwide and in Europe 2.4 million cases of cancer are reported per year, 50% of which are fatal.

In this proposal we present a chemical biology route to propel research in cancer biology forward so that new drug targets can be identified. This global aim will be achieved by using a multidisciplinary approach, which employs peptide synthesis, molecular biology, NMR spectroscopy, X-ray crystallography and other cutting-edge biophysical techniques. This project, which aims to synthesize different ER modified constructs for elucidating comprehensively the role of post-translational modifications in the development of breast cancer and resistance to tamoxifen, would be of high importance for advancing prevention, early detection, monitoring and treatment of the breast cancer disease.'

Introduzione (Teaser)

All the functions and dysfunctions in the body are mediated by chemical molecules, billions of them. New experimental techniques have now made it possible to study chemical modifications that play a role in breast cancer.

Descrizione progetto (Article)

Bringing together the fields of synthetic chemistry and biology forms the perfect union with which to study biological molecules involved in pathological processes. It is also uniquely positioned to design drugs according to biological targets.

Chemical biologists initiated the EU-funded project 'Using chemical-biology to synthesis and study nuclear receptor proteins' (CHEMBIONMR) to untangle some of the molecules and parts of molecules important in breast cancer. The focus was on oestrogen receptors (ORs). About 75 % of all breast cancers are ER-positive meaning that oestrogen causes them to grow.

Post-translational modifications (PTMs) of molecules occur after ribosomes translate the code of messenger RNA into specific amino acid chains. They play critical roles in the subsequent functions of many molecules and are important targets for drug therapies. They are also important to OR function.

Until now, it has been quite challenging to synthesise well-defined OR constructs containing PTMs. CHEMBIONMR accomplished this task, successfully introducing PTMs at one end of the OR ligand binding domain, the region of the OR that binds oestrogen. In order to probe the effects of the PTM on OR activity, researchers also introduced a fluorescent probe in a site-specific way.

Investigators employed a number of biophysical techniques (fluorescence polarisation, circular dichroism and nuclear magnetic resonance) and molecular dynamics simulations. The results revealed a PTM (phosphorylation)-dependent but ligand-independent pathway to OR activation.

This is particularly important in understanding why some forms of breast cancer are OR-negative and resistant to the drug tamoxifen. Tamoxifen is an OR antagonist, a molecule resembling oestrogen that competes with it at the OR ligand binding site. Administration of tamoxifen may not reduce cancer progression in some cases because OR activation is dependent on phosphorylation of the receptor, not ligand binding.

CHEMBIONMR has not only advanced understanding of breast cancer and mechanisms of activation of OR, providing a therapeutic target. It has also delivered important tools for studying the PTMs so critical to cellular signalling and molecular function. Outcomes are expected to speed the understanding of disease processes and the subsequent development of novel therapies with benefits for millions worldwide.

Altri progetti dello stesso programma (FP7-PEOPLE)

TRANSTEARA (2013)

Determining the role of gamete small RNAs in propagating the trans-generational epigenetic silencing of transposable elements

Read More  

EXOSOME-SKI-COMPLEX (2013)

Structural and functional studies on how the Ski complex activates the exosome to degrade RNA

Read More  

LAMP (2013)

Luminescence Amplification by Metal organic framework-Polyoxometalate composites

Read More