The cellular determinants of bone repair
The aim of this project is to understand to understand the different cell types that can contribute to bone formation and repair.
High-energy open fractures remain a challenge for orthopaedic treatment, with complications such as infection, delayed union, and non-union occurring in upwards of 10% of cases. The causes of poor open fracture repair are unclear, but a likely factor is a deficiency in cells able to contribute to new bone. The traditional paradigm is that bone progenitors primarily originate from the bone marrow and the periosteal layer that envelops bones. However, we have recently shown that myogenic progenitors are highly sensitive to bone signals in vitro, and that non-muscle cells can be sensitized to bone signals by forced expression of myogenic factors. We then used conditional reporter mice to demonstrate that myogenic progenitors can make an in vivo contribution in mouse models of ectopic bone formation and open fracture healing. We now seek to expand upon these discoveries with more mechanistic and functional studies- Aim 1: A variety of different progenitor cell populations are present within muscle tissue, including myogenic progenitors and vascular endothelial cells. We will undertake a range of in vitro experiments on progenitor populations isolated from muscle. These studies will clarify the functional roles of different BMP receptors in different progenitor cells. Our mechanistic BMP receptor experiments will also utilise siRNA gene knockdown and flow-cytometry approaches. Aim 2: We have completed a study using MyoD-cre:Z/AP mice to track the contribution of myogenic cells to ectopic bone formation and fracture repair. We now propose to examine at the contribution of vascular endothelial cells, as well as local cells versus circulating osteoprogenitors, using similar transgenic mouse models. Aim 3: Prior experiments showing considerable incorporation of myogenic progenitors into new bone led us to hypothesise that these cells are important for the early osteogenic response. To test this we are breeding double transgenic MyoD-cre:Osxflox/flox mice. In these mice, muscle progenitors are unable to make a functional contribution to bone. This allows us to directly test the involvement of myogenic progenitors in our range of established orthopaedic animal models. This timely study seeks to address several basic but important scientific questions about the functional contribution of different progenitor cells to bone formation.
Techniques used include cell culture, transgenic/knockout mouse analysis, molecular biology and protein chemistry. PhD scholarships/APA top-ups available, to be judged based on the strength of the applicant.
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Orthopaedics, Paediatrics, Bone healing, Fractures, Bone development, Bone cell biology, Cell biology, Movement, Genes in biology & medicine, cell culture, Genetic mouse models, Cre-Lox recombination, Flow cytometry
The opportunity ID for this research opportunity is: 890
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