About the Project
Osteoporosis and obesity are 2 major public health problems arising from dysregulation of MSCs which give rise to both osteoblasts and adipocytes. Osteoporosis results from disordered bone remodelling where the bone-resorbing activity of osteoclasts exceeds the bone-forming activity of an insufficient osteoblast pool. Similarly, an inability of subcutaneous (SC) white adipose tissue (WAT) to adequately expand - by recruiting new adipocytes from MSCs - and safely store lipid in the face of persistently positive energy balance, underlies the association between obesity, ectopic (visceral, muscle, liver) fat deposition, lipotoxicity and cardio-metabolic disorders [1].
WNTs are a family of secreted glycoproteins which bind to LRP5/6 receptors to activate the transcriptional co-activator β-catenin and WNT target gene expression. WNT signalling plays a key role in MSC biology, adipogenesis [1-3] and osteoblastogenesis. Missense mutations in LRP6 result in osteoporosis, visceral adiposity and cardiovascular disease (CVD). Similarly, loss-of-function LRP5 mutations lead to osteoporosis and an increased prevalence of type 2 diabetes. Reciprocally, we have shown that subjects with high bone mass (HBM)-associated LRP5 mutations exhibit lower-body fat accumulation and enhanced insulin sensitivity. Mechanistically, LRP5 modulates fat progenitor proliferation and differentiation in a depot-specific manner via dose-dependent effects on WNT/β-catenin signalling [4].
The aim of this project is to examine the role of LRP5-binding proteins in the regulation of MSC biology and by extension modulation of bone mass, body fat distribution and susceptibility to obesity-associated CVD.
The successful student will use a combination of in vivo human studies and in vitro experiments. Human studies will examine the effects of low-frequency and rare variants on bone mass, regional adiposity and metabolic profile. These will benefit from access to the Oxford Biobank (OBB); comprising DNA, clinical, biochemical, DEXA, and exome chip array data from >7500 volunteers and a national extreme HBM cohort (n=258). Experiments will include assessment of adipocyte number and size (histology) and determination of bone mass and fat distribution (DEXA), and insulin sensitivity (clamp studies). In vitro functional studies will determine the role of LRP5-interacting proteins in human MSC biology. We will utilise established, inducible lentiviral vector systems to stably over-express, knock-down, and edit (CRISPR Cas9) specific target genes in immortalised abdominal/gluteal and abdominal/visceral fat MSC pairs uniquely available within Oxlip. The effects of these genetic manipulations on WNT signalling, proliferation, differentiation (osteoblast/adipocyte), and apoptosis will then be assessed. Where appropriate, studies will be complemented by experiments with recombinant proteins and/or monoclonal antibodies.
Funding Notes
Funding for this project is available to basic scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.
For October 2017 entry, the application deadline is 6th January 2017 at 12 noon (midday).
Please visit our website for more information on how to apply.