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Project Co-ordinator:

Prof. Leszek Kaczmarek
http://neurogene.nencki.gov.pl
l.kaczmarek@nencki.gov.pl
Nencki Institute
Warsaw, POLAND

 

Project Manager:

Ms. Marta Rucinska
m.rucinska@nencki.gov.pl
Nencki Institute
Warsaw, POLAND

 

Recruitment Co-ordinator

Prof. Alexander Dityatev
alexander.dityatev@dzne.de
Deutsches Zentrum fur
Neurodegenerative Erkrankungen
Magdeburg, GERMANY

 

Training Co-ordinator

Prof. Robert Pawlak
R.Pawlak@exeter.ac.uk
University of Exeter Medical School
Exeter, UK

ESR6:    PAR-1 "ECM signalosome" and fear/anxiety (lead: UNEXE, partners: ENS, MPG, SVIDA)

Alberto Labrador-Ramos     

a.labrador-ramos@exeter.ac.uk

alberto_labrador.jpg

 

 

 

 

 

 

 

 

This PhD fellowship is available at the University of Exeter and will be supervised by Professor Robert Pawlak (www.pawlaklab.com). The project aims to determine the role of protease-activated receptor-1 (PAR-1) signalosome in the development of fear and anxiety in mice.

Mental disorders are the leading cause of disability and constitute 13% of the global disease cost. One-third of this burden is attributed to anxiety disorders and depression. Available cures are ineffective and current research strategies need re-focusing. A major obstacle to progress arises from the fact that conventional laboratory approaches provide only static snapshots of cellular dynamics and are insufficient to pinpoint the critical molecular elements of the disease.

Over the last ten years the Pawlak laboratory have provided evidence that extracellular proteases (tissue-plasminogen activator and neuropsin) and their receptors (protease-activated receptors or PARs) are critical for the development of stress-induced anxiety and fear (see references below). PAR-1 belongs to the family of G protein coupled receptors (GPCRs) and have one extraordinary feature: it mediates contrasting neuronal responses depending on the emotional status of an animal by a dynamic shift between distinct G protein coupling partners. Thus, PAR-1 is uniquely posed to regulate neuronal activity in experience-dependent manner (Figure 1). Our finding established experience-specific switch in GPCR/G protein-coupling in the amygdala as a novel mechanism regulating neuronal excitability and fear.

This PhD project will employ a combination of molecular biological, proteomic and behavioural approaches in mice to identify, characterize and manipulate dynamic molecular interactions of PAR-1, critical for the development of mood disorders.

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Using genetically modified (TAP-tagged) PAR-1 combined with pull-down methods and mass spectrometry, the student will determine PAR-1  signalosome and its contribution to anxiety/fear-induced PAR-1 signalling. Changes in PAR-1 signalosome will be examined using either native amygdala tissue or primary amygdalar neurons. Finally, the student will genetically prevent critical PAR-1 protein-protein interactions to manipulate fear/anxiety in mice.

For more information about research in the group, please see our website (www.pawlaklab.com) and the below articles:

  • Bourgognon J-M, Schiavon E, Salah-Uddin H, Skrzypiec AE, Attwood B, Shah RS, Mucha M, Challiss RAJ, Forsythe ID, Pawlak R. Regulation of Neuronal Plasticity and Fear by a Dynamic Change in PAR1 - G Protein Coupling in the Amygdala. Molecular Psychiatry 2013;18(10):1136-45.
  • Mucha M, Skrzypiec AE, Schiavon E, Attwood BK, Kucerova E, Pawlak R. Lipocalin-2 controls neuronal excitability and anxiety by regulating dendritic spine formation and maturation. PNAS 2011, 108(45):18436-41.
  • Attwood B, Bourgognon J-M, Patel S, Mucha M, Schiavon E, Skrzypiec AE, Young KW, Shiosaka S, Korostynski M, Piechota M, Przewlocki R, UPawlak RU. Neuropsin cleaves EphB2 in the amygdala to control anxiety. Nature 2011, 473(7347):372-5.
  • Poulin B, Butcher A, McWilliams P, Bourgognon JM, UPawlak RU, Kong KC, Bottrill A, Mistry S, Wess J, Rosethorne EM, Charlton SJ, Tobin AB. The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner. PNAS 2010, 107(20):9440-9445.

The University of Exeter (www.exeter.ac.uk) combines world class research with excellent student satisfaction at its campuses in Exeter and Cornwall. It is a member of the Russell Group of leading research-intensive universities. Exeter was voted the Sunday Times University of the Year 2012/13 & is ranked amongst the UK’s top 10 universities in the Higher Education league tables produced by the Times, the Guardian and the Sunday Times. Research at the University of Exeter Medical School is characterised by excellence. In each of our thematic areas, we seek to carry out research across the entire spectrum from basic biomedical research through mechanistic studies to patient-centred research.