Dear All Phd studentships available
Full details are at http://www.birmingham.ac.uk/schools/mds-graduate-school/scholarships/mrc-impact/index.aspx (closing date 16 January 2017). Any queries please email [email protected]<mailto:[email protected]> Investigating the platelet GPIb receptor as a nexus of molecular interactions in inflammation and innate immunity Supervisor: Jonas Emsley<https://www.nottingham.ac.uk/Pharmacy/People/jonas.emsley>, Mark Searle<https://www.nottingham.ac.uk/Chemistry/People/mark.searle>, and Natalie Poulter<http://www.birmingham.ac.uk/staff/profiles/cardiovascular-sciences/poulter-natalie.aspx> Summary: The glycoprotein (GP)Ib-IX complex is expressed exclusively on platelets and is the second most abundant receptor in the platelet membrane. Although GPIb primarily functions as a platelet receptor for von Willebrand factor (VWF), it can also act as receptor for other diverse ligands including thrombin, coagulation factor XI (FXI), factor XII, high-molecular-weight kininogen (HK) and cell receptors P-selectin, integrin αMβ2. The multiplicity of interactions has given rise to the concept that it can serve as a focal point or nexus for platelet function connecting multiple pathways as diverse as hemostasis and immune function. There is a growing interest in targeting the GPIb receptor as in animal models where it has shown the potential of reducing thrombus formation without compromising haemostasis, considered the holy grail of antithrombotic therapy, and provides a framework to treat diseases such as stroke. Here you will aim to advance the study of GPIb in the context of interactions with pro-inflammatory mediator HK. In this project you will use the complementary techniques of X-ray crystalllography (UoN), NMR and ITC (UoN) to study the GPIb-HK complex in vitro, together with cell based studies using super resolution light microscopy (UoB) to leverage greater understanding of GPIb. http://www.nottingham.ac.uk/research/groups/structural-biology/index.aspx Optimisation of coagulation factor XIIa inhibitors as potential anticoagulants devoid of bleeding side effects Supervisors: Peter Fischer<https://www.nottingham.ac.uk/pharmacy/people/peter.fischer>, Lodewijk Dekker<https://www.nottingham.ac.uk/Pharmacy/People/lodewijk.dekker>, Jonas Emsley<https://www.nottingham.ac.uk/pharmacy/people/jonas.emsley>, Claire Gibson<http://www2.le.ac.uk/departments/npb/people/cg95> Summary: The holy grail of anticoagulant therapy is to control thrombosis without compromising haemostasis. The activity of FXIIa (Hageman factor) initiates the contact activation (intrinsic) system of coagulation under pathophysiological conditions, as well as the kallikrein–kinin system in inflammation. FXII-deficient mice were found to be protected against arterial thrombosis, collagen- and epinephrine-induced thromboembolism, and ischaemic stroke. Extensive epidemiologic studies show that unlike other coagulation serine proteases, FXIIa coagulation activity is not implicated in the maintenance of haemostasis. Targeting FXIIa could also present novel therapeutic opportunities in combating increase thrombosis in Alzheimer’s disease. At present no selective FXIIa inhibitors are known and all currently used anticoagulation drugs have bleeding complications. The overall aim of the student project is to develop one of the series of our current FXIIa inhibitors with modest activity and selectivity to the point where compounds potentially suitable for evaluation in animal models of thrombosis have been identified. Currently compound design is based on modelled FXIIa structures and the student will participate in on-going X-ray crystallography studies whose aim is to crystallise fully activated FXIIa, as well as complexes with inhibitors. Obtaining such structures will significantly improve our current structure-based design methods. Eligibility In 'MRC Impact' * MRC Integrated Midlands Partnership for Biomedical Training (IMPACT)<http://www.birmingham.ac.uk/schools/mds-graduate-school/scholarships/mrc-impact/index.aspx> * Imaging: Molecules to Man<http://www.birmingham.ac.uk/schools/mds-graduate-school/scholarships/mrc-impact/imaging.aspx> * Complex Diseases: Cells to Systems<http://www.birmingham.ac.uk/schools/mds-graduate-school/scholarships/mrc-impact/complex-diseases.aspx> * Precision Medicine: Pathology to Population Health<http://www.birmingham.ac.uk/schools/mds-graduate-school/scholarships/mrc-impact/precision-med.aspx> * Eligibility<http://www.birmingham.ac.uk/schools/mds-graduate-school/scholarships/mrc-impact/eligibility.aspx> * How to applyResidence requirements for MRC studentships:<http://www.birmingham.ac.uk/schools/mds-graduate-school/scholarships/mrc-impact/apply.aspx> * British nationals who have lived in the UK all their lives are eligible. * Also eligible are non-British nationals who have settled status AND have been resident in the UK for 3 years immediately prior to the date of the start of the course. * EU nationals who have been ordinarily resident in the UK and Islands for three years immediately prior to the date of start of the course are eligible. * EEA and Swiss nationals (EEA migrant workers) should refer to the full RCUK guidelines<http://www.mrc.ac.uk/skills-careers/studentships/studentship-guidance/student-eligibility-requirements/> to check eligibility Academic requirements * Those who have a 1st or a 2.1 undergraduate degree in a relevant field are eligible. * Those who have a 2.2 and an additional Masters degree (Merit or Distinction) in a relevant field may be eligible. * Those who have a 2.2 and at least three years postgraduate experience in a relevant field may be eligible. * Those with degrees abroad (perhaps as well as postgraduate experience) may be eligible if their qualifications are deemed equivalent to any of the above ################################## Dr Jonas Emsley Professor of Macromolecular Crystallography, Division of Medicinal Chemistry & Structural Biology, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, University Park, Nottingham. 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