About the Project
NDORMS 2019/5
The extracellular matrix (ECM) is a complex, three-dimensional, non-cellular structure that is present in every organ in the human body. The ECM is composed of over 40 collagen subunits, 36 proteoglycans, and over 200 complex glycoproteins.
Elastic fibers are the principal components of connective tissue that impart resilience and elasticity to the skin. Elastin, an insoluble polymer of the monomeric soluble precursor tropoelastin, is the main component of elastic fibers in matrix tissue where it provides elastic recoil and resilience to a variety of connective tissues, e.g., aorta and ligaments. Elastic fibers regulate activity of TGFβs through their association with fibrillin microfibrils. Elastin also plays a role in cell adhesion, cell migration, and has the ability to participate in cell signaling. Fibrillins represent the predominant core of the microfibrils in elastic as well as non-elastic extracellular matrices, and interact closely with tropoelastin and integrins. Fibrillin is important for the assembly of elastin into elastic fibers. Fibulins are tightly connected with basement membranes, elastic fibers and other components of extracellular matrix and participate in formation of elastic fibers.
The ECM is a dynamic structure, and the production, degradation and remodelling of the ECM are tightly controlled under physiological conditions. Cleavage of ECM is achieved by multiple different protease families, such as Matrix Metalloproteinases (MMPs), Adamalysins (ADAMs, ADAMTS), Astacins (Meprins). These enzymes may be membrane bound or secreted. They not only break down ECM components, but in some instances are responsible for correct maturation of ECM components – for example ADAMTS2, 3, and 14 are involved in pro-collagen processing. Thus, elastic tissue physiology is governed by a balance between anabolic pathways (including gene expression and fibre assembly) and catabolic pathways (including proteolysis). Derangement of this system may lead to cutaneous and systemic disorders that show elastic tissue pathology.
There are several single gene disorders that affect the elastic tissue. For example, Ehlers-Danlos syndromes are a group of disorders characterised by hypermobile joints, hyperelasticity of the skin, arterial and venous dilatation, hernia and prolapse. The disorders are caused by mutations in collagens and their modifying enzymes. Marfan syndrome is an autosomal dominant disorder caused by mutations in the gene that makes Fibrillin. Typical features include tall stature with long slender limbs, hypermobile joints, aortic dilatation, heart valve failure, and herniae.
Aside from these single gene disorders, there are several common disorders of the elastic tissues which have a polygenic, multifactorial genetic basis. These conditions are much more common within the population, and understanding their genetic basis may lead to new therapeutic options. Examples of such conditions include varicose veins, uterine prolapse, abdominal herniae, haemorrhoids, and abdominal aortic aneurysms.
The study of complex disease has been revolutionised in the UK by the UK Biobank resource. This a prospective cohort study of ~500,000 individuals from the UK, aged between 40-69, who have had whole-genome genotyping undertaken, and have allowed linkage of these data with their medical records. For common elastic tissue diseases, there are sufficient affected individuals to allow for power to discover novel variants predisposing to disease.
Research Aims
1. To perform a genome-wide association study (GWAS) of each individual complex elastic tissue disease using UK Biobank data, after matching cases to unique controls for each condition.
2. To use meta-analysis methods (ASSET, CPAssoc, FEMA) to discover areas of genetic overlap between the different elastic tissue disorders and discover common pathways between the conditions.
3. To attempt to replicate associated variants in independent cohorts (e.g. DECODE, 23andMe) where possible.
4. To look for expression of key genes identified in 1 and 2 in affected and normal relevant human tissues collected during surgical procedures.
Details on specific training opportunities relevant to the project
The Botnar Research Centre plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which enables and encourages research and education into the causes of musculoskeletal disease and their treatment. A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome. All students are required to attend a 2 - day Statistical and Experimental Design course at NDORMS. The student will attend regular seminars within the department and those relevant in the wider University.
The student will receive training in relevant related research methodology, including the handling and analysis of large genetic datasets, advanced genetic techniques including cross-phenotpye analysis and Mendelian Randomisation. Additional on the job training opportunities will arise, and the supervisors will encourage the student to pursue such opportunities. Attendance at formal training courses will be encouraged. In addition, courses from the Oxford Learning Institute and the Oxford University Computer Sciences on generic skills for scientific research will be available and encouraged. Students will be expected to present data regularly in the departmental PGR seminars, Furniss group meetings, and to attend external conferences to present their research globally.
Contact details of potential supervisors
Dominic Furniss: [Email Address Removed]
Krina Zondervan: [Email Address Removed]
How to Apply
The department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisors or the Graduate Studies Officer, Sam Burnell ([Email Address Removed]), who will be able to advise you of the essential requirements.
Interested applicants should have or expect to obtain a first or upper second-class BSc degree or equivalent, and will also need to provide evidence of English language competence. The application guide and form are found online (https://www.ox.ac.uk/admissions/graduate/applying-to-oxford/application-guide?wssl=1), and the DPhil or MSc by research will commence in October 2019.
For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.
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