Control of bone shape and function by the extracellular matrix Fibrillin-1

Description

Bones are tightly regulated structures that remodel their structure to adapt to changes in their mechanical environment. With ageing, this mechanical response is often dampened, leading to bone loss and weakness. Fibrillin-1 is an extracellular matrix protein found in connective tissues, including bone. Mutations in fibrillin-1 leads to Marfan syndrome, which includes clear musculoskeletal defects such as longer and thinner bones, supporting a role for fibrillin-1 in controlling bone structure.

This project aims to define how fibrillin-1 controls bone structure. We hypothesise that fibrillin-1 is critical in the mechanoresponses of bone during the lifecourse, and that lack of fibrillin-1 leads to low bone mass.

This project is a multidisciplinary project with both in vivo murine experiments and assessment of bone mechanical properties, alongside computer modelling based at the University of Liverpool (Dr Blandine Poulet and Dr Alana Sharp) and in collaboration with Newcastle University (Dr Kasia Pirog).

Male and female transgenic mice where fibrillin-1 gene (FBN1) is deleted in limbs only (using PRX1-Cre; FBN1 KO) will be used to: define how FBN1 loss affects bone mechanical properties and structure across the lifecourse of the animal, and to understand if FBN1 is involved in cell responses to the mechanical environment. A variety of methods will be used to test these aims, including micro-CT imaging, Atomic Force microscopy, electron microscopy, organoids and 3D cultures of bone cells under dynamic compression, cell signalling analysis, and computer modelling of bone structure and mechanical environment.

To apply: please send your CV and a covering letter to Dr Blandine Poulet b.poulet@liverpool.ac.uk