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DEVELOPMENT OF IN VITRO 3D WHITE ADIPOSE CELL CULTURE MODELS FOR INVESTIGATING WHITE ADIPOSE CELL BIOLOGY AND GENETICS OF FAT DISTRIBUTION

 Lead supervisor: Prof Roger Cox, MRC Harwell Institute, Oxfordshire

Commercial partner: OxSyBio Ltd, Harwell Campus, Oxfordshire

 

This is an exciting opportunity to be part of the novel development of 3D printed living mammalian tissues for use in research and the clinic. The D.Phil. will be supervised jointly by the prestigious Medical Research Council Harwell Institute and the new thriving and highly innovative company OxSyBio. 

Adipose tissue is an important organ that stores lipid that can be mobilised to produce energy as required. Adipose tissue is also a source of hormones that regulate food intake and insulin sensitivity. Specialised fat cells can also generate heat through uncoupling of mitochondrial respiration. Dysfunction of adipose tissue, due to environmental and/or genetic factors, can lead to fat being stored in the wrong place and increased risk of type 2 diabetes (T2D) and cardiovascular disease. Human genome-wide-association (GWA) has identified >403 T2D and >500 body mass index (BMI)/ waist-hip-ratio (a measure of fat distribution) risk loci.

A major challenge is how to investigate genetic determinants of fat distribution and the mechanisms that control fat storage and metabolic signalling. Simple cellular 2D culture systems are useful in mechanistic studies but clear phenotypic differences to in vivo tissue limits their usefulness. To bridge the gap between 2D and in vivo tissue, the Cox Laboratory and OxSyBio (a small and medium enterprise company (SME) established in 2014) have collaborated to develop and optimise a 3-dimensional (3D) bio-fabrication adipose culture system.

The primary aim of this project is to improve our 3D model to obtain and fully characterize an ‘organoid’ type system in which we can manipulate genes, environment and apply treatments experimentally. This is in order to understand the basic mechanisms of fat deposition and function. Firstly, we will add other cellular components critical for fully functional white adipose tissue, including endothelial vascular cells and macrophages. Then we will evaluate these systems in response to known in vivo signals for lipogenesis, lipolysis, energy expenditure (measured using a Seahorse XFe96 analyser) and drug response.

We will further increase the utility of the system by introducing genetic mutations in candidate genes for altered fat distribution as part of ongoing waist-hip-ratio GWA locus work in the Cox laboratory. This exploits data from metabolic GWA to understand predispositions to disease.

A final goal is to humanise the system using induced pluripotent stem cells or cultured primary cells with a view to developing and validating a high throughput therapeutic screening system for biologically active compounds and proteins.

This research project is highly collaborative and the student will work at both the MRC Harwell Institute and OxSyBio which are a short walk apart. The MRC Harwell Institute is an international centre for mouse genetics at the forefront of studies in mouse functional genomics and mouse models of human disease. They are engaged in lifetime studies, from developmental abnormalities through to diseases of ageing. Training is available in a range of skills from genome editing, phenotyping, physiology, anatomy, histopathology, imaging, genomics, transcriptomics, proteomics, molecular biology, cell biology and cell culture. OxSyBio is a company developing 3D cell printing techniques to produce a range of tissue-like and functional tissues for medical research and clinical applications. Their vision is to ultimately produce tissues that can be used in the clinic for organ repair or replacement. There is also access to other facilities on the wider Harwell site including advanced microscopy techniques such as light sheet. The student will receive training in both basic-science research and with OxSyBio, in product focused research and its applications in a business environment. Finally, the project uses robotic and automated approaches in which the student will gain key skills.

The MRC Harwell Institute currently has 27 doctoral training students. The student will be registered in the Department of Physiology Anatomy and Genetics (DPAG).

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