PhD Research Studentships
Interaction of ECM nanomechanics and chondrocyte primary cilia in osteoarthritis. (Institute of Bioengineering PhD Studentship)
| Supervisor: | h.gupta@qmul.ac.uk,m.m.knight@qmul.ac.uk |
| Apply by: | 1 June 2013 |
Description
The alteration of mechanical interactions between chondrocytes and the extracellular matrix (ECM) is believed to play a significant role in the pathophysiology of degenerative and inflammatory conditions such as osteoarthritis (OA) [1]. The ECM of cartilage can be considered, mechanically, as a nanoscale composite of Type I/II collagen, proteoglycans and other noncollagenous proteins. In pathological conditions like OA, it is believed that (i) abnormal alterations in the ECM are induced by altered synthesis of ECM, mediated by structures such as primary cilia [2] and (ii) the altered matrix properties will in turn influence subsequent chondrocyte mechanotransduction and differentiation, as well as the migration of inflammatory cytokines like IL-1. However, the precise mechanisms by which the interaction between cellular structures (such as primary cilia [2]) and the cartilage microenvironment occur in normal and osteoarthritic tissue is not well understood. The mechanistically crucial zone determining the interaction between ECM and primary cilia is at the chondrocyte/ECM interface, over a zone of a few microns [2]. Resolving the nanomechanics of the ECM matrix at this scale is beyond the resolution of the majority of microscopic methods, due to limitations of wavelength and statistics. A powerful new approach to determine cell/tissue mechanics at this interface is through the use of real-time microfocus X-ray diffraction using high brilliance synchrotron radiation, combined with in-situ mechanical testing [3]. This PhD project aims to understand the interaction of abnormal nanomechanics of the ECM at the chondrocyte/ECM interface with changes in primary cilia and function, to understand the role of this interaction in disease progression in OA. The work programme for the PhD student will provide a multidisciplinary training combining state-of-the-art ultrastructural, biomechanical and cellular biochemistry techniques, to address the following research objectives: Objective 1 - Use cartilage tissue from cilia mutant and OA mice models to look at the interaction between the nanomechanics of cartilage and the cilium and specific associated genes which regulate cilia structure. Objective 2 - Identify how changes in cilia structure associated with pathological mechanical or inflammatory stimuli regulate tissue mechanics. This objective is complementary with an existing MRC grant application (Knight) on the effect of the alterations in the physiochemical characteristics of the cartilage microenvironment on PC structure, functionality and downstream synthesis of ECM. Objective 3 - Determine how pharmaceutical regulators of cilia structure influence nano-mechanics Methodology: Cartilage nanomechanics will be analysed using in situ synchrotron small-angle X-ray diffraction (SAXD) and wide-angle X-ray diffraction (WAXD) during mechanical loading of tissue explants maintained in a viable state in a purpose-built bioreactor. The technique (developed by Gupta) enables direct measurement of the mechanics of the cartilage microenvironment via determination of (i) fibrillar strain and (ii) fibril reorientation in the ECM. Fibril strain is determined from percentage shifts in axial intensity distributions and fibril reorientation from changes in angular intensity distributions, respectively, of the meridional Bragg spectra of type II collagen (preliminary, unpublished data on bovine cartilage). This method has been successfully applied by our group previously to determine both fibrillar strain and interfibrillar shear in the ECM of mineralized tissues and tendons [2]. Cilial structure will be quantified from 3D confocal imaging and super resolution 3D-structural illumination (SIM), and protein expression via super resolution immunofluorescence microscopy. Associated alterations in signalling will be tracked with a range of techniques including qPCR, western blot and confocal cilial localization. References: [1] D. E. Ingber 2003, Ann. Med. 35:564-577 [2] A. K. T. Wann and M. M. Knight, Cell. Mol. Life Sci. (2012) 69:2967-2977 [3] H. S. Gupta et al, J. Bone Miner. Res. 27:876-890 (2012); H. S. Gupta et al, J. Struct. Biol. 169:183 (2010); H. S. Gupta et al, Proc. Natl. Sci. Acad. 103: 17741 (2006). For informal enquiries about this position, please contact: Dr Himadri Gupta, E-Mail: h.gupta@qmul.ac.uk Dr Martin Knight, E-Mail: m.m.knight@qmul.ac.uk QMUL Institute of Bioengineering This PhD studentship is offered through the QMUL Institute of Bioengineering which is a new cross-faculty initiative bringing together over 40 academics from the faculties of Medicine & Dentistry and Science & Engineering. The Institute will provide a focus for ground-breaking research aimed at the development of new medical technologies to meet the key healthcare challenges of the 21st century. There are three research themes namely: ‘medical devices and biomonitoring’, ‘biomaterials and interfaces’ and ‘biomechanics and mechanobiology’. QMUL Research Studentship Details • Available to Home/EU/International Applicants • Full Time research degree programme only • Applicants will be required to start the degree programme in September/October 2013. • The studentship arrangement will cover tuition fees and provide an annual stipend (£15,590 in 2012/13) for up to three years. • The minimum requirement for this studentship opportunity is a good Honours degree (minimum 2(i) honours or equivalent) or MSc/MRes in a relevant discipline. • Students must be able to demonstrate “a capability to undertake and benefit from research training through to completion, to the standard necessary to qualify for a PhD.” • International applicants should refer to the following website at http://www.qmul.ac.uk/international/index.html • If English is not your first language then you will require a valid English certificate equivalent to IELTS 6.5+ overall with a minimum score of 5.5 in all sections (Reading, Listening, Writing, Speaking). Application Method: To apply for this studentship and for entry on to the Medical Engineering PhD programme (Full Time, Semester 1 start) please complete the online application form: https://mysis.qmul.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RFQM-H3ZM-09&code2=0004&code3=GUEST During the online application process you will be asked to provide details of any funding you are applying for, please be sure to include a reference to ‘2013 BIOENGINEERING’ to associate your application with this studentship opportunity. For General Enquiries in regards to the application process please email the SEMS Research Administrator, Mr Jonathon Hills on j.hills@qmul.ac.uk
Eligibility
- The minimum requirement for this studentship opportunity is a good honours degree (minimum 2(i) honours or equivalent) or MSc/MRes in a relevant discipline.
- If English is not your first language, you will require a valid English certificate equivalent to IELTS 6.5+ overall with a minimum score of minimum score of 6.0 in each of Writing, Listening, Reading and Speaking).
- Candidates are expected to start in (Semester ).
Contact
For informal enquiries about this opportunity, please contact h.gupta@qmul.ac.uk,m.m.knight@qmul.ac.uk.
| Related website: | http://www.bioengineering.qmul.ac.uk/ |