SLMS Academic Careers Office
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- 1. Bayesian Modelling of Disease Progression In juvenile dermatomyositis (JDM)
- 2. Mind-body interactions influencing the outcome of treatment for epilepsy
- 3. Treating retinal inflammation: bridging the divide between common problems in the eye and the brain
- 4. Development of a Novel In Vivo Animal Model for Schizophrenia Drug Testing
- 5. Immune mechanisms in Developmental Programming of Non-Alchoholic Fatty Liver Disease
- 8. Using social media big data to understand the genetic and environmental aetiology of mental health and disorder in emerging adulthood
- 10. Molecular Control of Pain Processing
- 11. Understanding the mechanisms of insulin secretion in patients with HADH mutations
- 12. Origins of cortico-subthalamic “hyperdirect” pathway in the motor cortex: electrophysiology and imaging
- 13. The mechanical control of tissue regeneration.
- 14. Investigating community severance in Southend and its effects on health and access to healthcare
- 15. Ageing of the liver and protection from injury: from flies to mice to humans
- 16. Intelligent nanomaterials against antibiotic resistant bacteria
- 17. Retroviral restriction factors that control species-specific gene regulation and stem cell fate
- 18. Improving women’s choice and uptake of effective contraceptive methods through development of interactive digital interventions
- 19. From embryonic cell to neuron: understanding the complexity of developmental decisions
- 20. Identification of mitochondrial biomarkers and therapeutic targets in pancreatic cancer
- 23. Television subtitling for deaf and hearing-impaired viewers: a route to improve English language skills for UK migrants with normal hearing
- 24. Large-scale phylogenomic mapping of domain architecture changes to elucidate gene function evolution
- 25. Calcium channel trafficking, nociceptive neurotransmission and mechanism of action of gabapentinoid drugs in mouse models of neuropathic pain
- 26. Real-time and nanometre-scale visualisation of membrane perforation in pathogen attack and immune response
- 22. Understanding the molecular mechanisms of pancreatic cancer progression
- 27. Forming a sensory map: the role of auditory and visual cues in the hippocampal representation of space
- 29. Human amniotic fluid-derived induced pluripotent stem cells for the treatment of osteogenesis imperfecta.
- 31. Understanding the immunopathogenesis of juvenile-onset SLE: could targeting lipid biosynthesis control disease progression and reduce cardiovascular risk?
- 30. Shared Control Wheelchair Interfaces
- 32. Understanding the neurobiological effects of clinical photochemical internalisation in order to minimise nerve damage during treatment of cancer
- 33. Shedding light on the ethnic attainment gap: The influence of intercultural relations on students’ learning and performance
- 34. Patient-focused development of a versatile, wearable neurostimulation device to control urinary incontinence.
- 35. The development and evaluation of positive psychology outcome measures for people with dementia
- 36. Rehabilitation strategies to improve balance and prevent falls in people with Charcot-Marie-Tooth disease
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Supervisor Pair: Pascale V Guillot and Timothy R Arnett Potential Student’s Home Department: Institute for Women's Health
Babies with brittle bone disease, or osteogenesis imperfecta (OI), are born with fragile bones that break easily. For most babies with OI, everyday activities can lead to fractures at any time, often from little or no apparent cause. All affected babies experience other problems, including muscle weakness, hearing loss, curved bones, scoliosis, brittle teeth, skeletal deformities, and respiratory problems. OI starts to manifest before birth in utero, lasting throughout a person’s lifetime. It is diagnosed commonly at the mid-pregnancy, high-resolution fetal ultrasound scan, where the characteristic short long bones and fractures are already present and detectable. Around one baby in every 10,000 is affected in the UK.
There is at present no cure for OI. The only pharmaceutical treatments are palliative, failing to address the underlying bone brittleness.
OI is caused by genetic mutations that affect the production of collagen type I, the main component of the bones. Bone is a composite formed of the organic matrix (dense collagen type I fibres produced by osteoblasts) that provides tensile strength and hard minerals (mainly hydroxyapatite) that are added to the matrix to provide compressive strength. Because of this structure, the bones can bend and recover their shape, and carry the weight of an individual without breaking. In OI patients, the collagen is abnormal and mineralization is disorganized. As a consequence, the bones become brittle and break sharply without plastic deformation.
We have used an experimental model of OI (oim mice), which suffer from fragile bones and multiple fractures identified at birth. We have been able to decrease fracture rate by two-third by transplanting oim mice in utero with human mesenchymal stem cells (MSCs). As a result, oim bones were stronger and break less easily. We also showed the donor cells became bone cells in oim mice and participated to bone formation. Because we need considerably more cells to treat humans than mice, we need to expand the cells in vitro before transplantation to treat human babies. Unfortunately, these cells cannot be expanded to large numbers without losing their capacity to regenerate bones.
In this project, you will first reprogram human cells to pluripotency (induced pluripotent stem cells, iPS cells). As a result, these rejuvenated cells will regain the capacity to be expanded to large numbers without aging and without losing their regenerative characteristics. You will then transplant these cells in oim fetuses to evaluate their bone repair and regeneration potential (prenatal cell therapy) and determine optimal timing of injection (prenatal vs. perinatal vs. late postnatal). Finally, using optimal timing of transplantation as determined above, you will assess whether a second transplantation is required to maintain the long-term therapeutic benefits of the first iPSC-MSCs injection. This pre-clinical project will pave the way for human trials for OI using translatable iPSC technology. We anticipate 3 publications to high impact factor peer-reviewed journals. The project will be co-supervised by Professor Tim Arnett, who is a leading expert on osteoblast and osteoclast function, and by Dr Pascale V Guillot, whose group was the first to reprogram human cells to pluripotency using chemicals only, without ectopic expression of transcription factors. Together they run projects to develop iPS cell-based therapy to treat bone pathologies.