ESR1
    ESR2
    ESR3
    ESR4
    ESR5
    ESR6
    ESR7
    ESR8
    ESR9
    ESR10
    ESR11
    ER1
    ER2
    ER3


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

ESR5:    The role of PAR-1/ECM interactions in neuronal remodelling (lead: UNEXE, partners: NENCKI, UCL, ETEC)

Valentina Brambilla   

v.brambilla@exeter.ac.uk

Valentina.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) and its partners in experience-induced dendritic and spine plasticity in the amygdala.

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.

PAR-1 interacts with numerous molecules at the neuron-extracellular matrix interface. The student will characterise the contribution of PAR-1 and its molecular interactions to stress-induced plasticity at the cellular level.

The student will either enhance or disrupt critical PAR-1/ECM/protease interactions in the amygdala by circuit-specific viral delivery of native or binding-incompetent PAR-1, proteases or ECM variants. Animals will then be subject to either innate (restraint stress) or conditioned fear (cued and contextual) paradigms. To determine the roles of individual PAR-1 modulators in experience-induced dendritic morphogenesis, the student will label neurons post hoc in acute amygdala slices and analyze dendritic and spine morphology using 3D confocal microscopy. The student will next examine the multi-factorial relationships between these morphological changes and the development of anxiety.

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.