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Understanding the role of coagulation factor XIII in the development of venous and arterial thrombosis

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  • Full or part time
    Dr Duval
    Dr Ariens
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Blood clots that occur during myocardial infarction and deep vein thrombosis are leading causes of death worldwide. FXIII plays an important role in clot stabilisation by cross-linking fibrin, resulting in increased resistance of the clot to mechanical and proteolytic challenges. A FXIII-A single nucleotide polymorphism, Val34Leu is associated with decreased risk of myocardial infarction, and a weak protective effect on venous thromboembolic disease.

The genes encoding for both A- and B-subunits are highly polymorphic. The most common single nucleotide polymorphism, FXIII-A Val34Leu, is located in the activation peptide and has been linked with an overall protective effect on thrombotic disease. Meta-analyses have shown that FXIII-A Val34Leu is associated with decreased risk of myocardial infarction and coronary artery disease. FXIII-A Val34Leu has also been associated with a weak protective effect on venous thromboembolic disease. Our group previously showed that the FXIII-A 34Leu variant purified from plasma increases activation rates by thrombin, and alters fibrin clot structure in-vitro, when compared to the most common variant 34Val1.

Our most recent study has shown that the effects of FXIII-A 34Leu on thrombus formation in-vivo are related to its intrinsic effects on cross-linking within the clot, via increased cross-linking, whereas no significant changes in thrombus size were observed2.

We propose that the cardioprotective effects of FXIII-A Val34Leu may not be related to reduced thrombosis, but rather to an increased stabilisation of the atherothrombotic plaque or the fibrin clot, via increased cross-linking of the plaque and clot components. The pathogenesis of atherothrombosis involves inflammation, macrophages infiltration, lipid deposition and generation of an atherosclerotic plaque, which triggers platelets activation and coagulation upon rupture. Several components of the atherosclerotic plaque such as fibrin(ogen), collagen and fibronectin have been shown to be FXIII substrates.

Venous thromboembolic disease pathogenesis is different to that of arterial thrombosis, and involves immobilisation, stasis, inflammation and hypercoagulability. Parts of the thrombi formed in the deep vein may break and embolise downstream, particularly in the lung (pulmonary embolism). In this case, we propose that FXIII-A Val34Leu stabilises the thrombus by increasing cross-linking of the fibrin fibres, making the clot more resistant to mechanical strain, and decreasing fibrinolysis by increasing cross-linking of fibrinolysis inhibitors such as 2-antiplasmin to the clot. Both activities of FXIII-A Val34Leu would prevent rupture of the clot, and protect against thromboembolism.

The focus of the current project is to investigate the role of FXIII-A WT and Val34Leu in medium- and long-term thrombotic processes. The successful applicant will develop new animal models of atherothrombosis (ApoE-/- mice) and venous thrombosis (Inferior Vena Cava ligation), already described elsewhere, at the University of Leeds. Making use of these models and our currently available FXIII-A-/- mice, the role of FXIII-A WT and V34L will be further investigated. Recombinant FXIII WT and V34L proteins will be expressed in E. coli. In addition, hydrodynamic gene transfer will be used to investigate FXIII variants in vivo.

The student will receive full training on all the technics and methods used, as well as attending the full Home Office Module 1-4 training (if required).

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject. This project would suit a student with a strong background in computational statistics/bioinformatics and training in genomics.

The Faculty minimum requirements for candidates whose first language is not English are:

• British Council IELTS - score of 6.5 overall, with no element less than 6.0
• TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

To apply for this scholarship applicants should complete a Faculty Scholarship Application form using the link below http://medhealth.leeds.ac.uk/download/2376/fmh_scholarship_application_16_17_entry and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School [email protected]

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly to [email protected] by no later than Monday 29 February 2016.

If you have already applied for other scholarships using the Faculty Scholarship Application form you do not need to complete this form again. Instead you should email [email protected] to inform us you would like to be considered for this scholarship project.

Any queries regarding the application process should be directed to [email protected]

Funding Notes

This Alan and Joan Webster scholarship will cover the cost of tuition fees (UK/EU rate) and an annual tax-free stipend of £14,057 for up to 3 years, subject to satisfactory progression.

References

1. Ariens RA, Philippou H, Nagaswami C, Weisel JW, Lane DA, Grant PJ. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood. 2000;96(3):988-95.

2. Duval C., Ali M., Chaudhry W.W., Ridger V.C., Ariëns R.A.S., Philippou H. Factor XIII A-subunit V34L variant affects thrombus cross-linking in a murine model of thrombosis. Arterioscler. Thromb. Vasc. Biol. ATVB, In Revision.

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