Abdominal aortic aneurysms (AAAs) are permanent dilations of the aorta that exceed 50% of the original size of the vessel or that are greater than 3cm in maximum diameter. After a period of asymptomatic expansion, rupture of AAA can occur with an associated mortality rate as high as 90% in developed countries. AAAs are characterized by chronic inflammation, extracellular matrix (ECM) protein remodeling, intravascular hematomas and atherosclerosis. The ECM proteins, collagen and elastin, are the most abundant structural proteins of the arterial wall. They provide tensile strength and elastic recoil to the arterial wall. Turnover of the ECM proteins, and particularly, the balance between degradation and synthesis is vital for preserving the structural integrity of the aortic wall. Deregulation of ECM synthesis and degradation is thought to be crucial for the development and outcome of AAAs. Collagen is a major ECM protein involved in AAA remodeling. Following vascular injury, myofibroblasts and other cell types synthesize pro-collagens, mostly type 1 and type 3. Pro-collagen proteinases initially convert these precursor molecules into collagen fibers which subsequently become cross-linked into collagen fibrils by lysyl-oxidase. In parallel, upregulation of matrix metalloproteinases (MMPs) causes ECM degradation that not only facilitates adaptive changes (including removal of cellular debris by inflammatory cells and migration of myofibroblasts) but also contributes to weakening of the myocardium and ventricular dilatation. Thus, a fine tuned balance of collagen turnover is crucial for AAA remodeling and vascular integrity.
This project will investigate the role of collagen I and III in the evolution and instability of AAA and the potential impact of therapies that aim in modulating the fibrotic response using in vivo molecular MRI, SPECT-PET and ex vivo techniques.
Person Specification The ideal applicant will have an undergraduate/masters degree in a biomedical, biological or biochemical discipline and proven experience working with imaging (MRI, PET) and biological techniques. Experience of vessel wall biology and/or rodent models is desirable, as is demonstrable experience of working as part of a multi-disciplinary team. They should have a commitment to research and hold or realistically expect to obtain at least an Honors/ Upper Second Class Honours Degree.
Starting dates: 01/10/2029, 01/01/2020 and 01/04/2020
Fully funded 3.5 year Full-time PhD studentship (including home/EU tuition fees, annual stipend and consumables)
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