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for a 3
is a greater
as a result
1) to analyse
RA on bone
RA on bone
3) to establish
Contact & Principal Supervisor: Prof Colin Farquharson - firstname.lastname@example.org
Tel: 0131 651 9176.
Co-supervisor: Dr Vicky MacRae - email@example.com
Bone formation is a carefully orchestrated process mediated by promoters and inhibitors of the mineralisation process. If the process is not properly regulated, the result can be too little of the mineral or too much - either of which can compromise bone health. Tissue-nonspecific alkaline phosphatase (TNAP) plays a crucial role promoting mineralisation of the collagenous extracellular matrix by restricting the concentration of the calcification inhibitor inorganic pyrophosphate (PPi). PHOSPHO1 – an enzyme discovered at the Roslin Institute – is a phosphatase with specificity for phosphoethanolamine and phosphocholine and has a role in scavenging Pi from matrix vesicle (MV) membrane phospholipids to favour intravesicular mineral deposition. Phospho1 knockout mice display spontaneous bone fractures, bowed long bones, osteomalacia and scoliosis in early life. Importantly, ablation of both TNAP and PHOSPHO1 function leads to complete absence of skeletal mineralisation (Huesa et al. 2011; Yadav et al. 2011). It is the aim of this studentship to determine how TNAP and PHOSPHO1 cooperatively work together to promote bone mineralisation This hypothesis-driven studentship will determine if the first step of MV mineralisation involves the convergence of two independent biochemical pathways a) intra-vesicular Pi generation by the enzymatic action of PHOSPHO1 and b) influx of Pi generated in the perivascular space by the activities of TNAP and NPP1, via phosphate transporters.
This project has relevance to ageing and animal health.
This project will involve training in various cellular and molecular biology techniques and will include in vivo studies with mice and in vitro approaches such as cell culture, immunohistochemistry, in situ hybridisation, western blotting, quantitative PCR and DNA transfection studies.
Identifying novel genes controlling vascular calcification
The Roslin Institute, University of Edinburgh
This studentship is for 4 years and is available from Sept 2012.
Further enquires should be made to Dr Vicky MacRae – firstname.lastname@example.org
Vascular calcification (VC) is a significant risk factor in the development of cardiovascular disease, and involves the deposition of calcium phosphate mineral in arteries and cardiac muscle. VC has severe clinical consequences, however, the mediators and mechanisms of VC have yet to be fully elucidated. Many of the underlying principles on calcification are based on our understanding of bone mineralisation, which occurs through hydroxyapatite deposition in the extracellular matrix. This depends on a regulated balance of factors such as calcium and inorganic phosphate concentrations, in the presence of matrix proteins and mineralisation inhibitors including inorganic pyrophosphate and osteopontin.
Microarray analysis recently undertaken in our laboratory has identified a number of potential novel genes that are associated with vascular calcification. The characterisation of these genes will be the focus of this project. Functional data will be obtained from in-vitro models. We will study the calcification potential of cultured primary VSMCs and/or VSMC lines and undertake gain and loss of function studies. Where appropriate transgenic mouse models will also be used.