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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
- 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
- 26. Real-time and nanometre-scale visualisation of membrane perforation in pathogen attack and immune response
- 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?
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Supervisor Pair: Bart Hoogenboom / Alan Lowe and Helen Saibil Potential Student’s Home Department: Research Department of Structural and Molecular Biology
This project aims to visualize the assembly pathways of pore forming proteins and gain mechanistic insight in the effects of potential drugs and vaccines against bacterial toxins and of pore-forming protein deficiencies in the immune system.
Pore-forming proteins are crucial armaments in the continuous battle between organisms and their pathogens. In the course of their function, they assemble into oligomeric rings that puncture holes through their target membranes. For example, pore-forming bacterial toxins are proteins that perforate host cell membranes to release nutrients for the bacteria, to invade the host cell or to kill it. On the other hand, the immune system secretes pore-forming proteins to kill infected or cancerous cells, or invading pathogens, in the organism.
In particular the dynamics of membrane pore formation remain enigmatic, primarily due to the lack of high-resolution, dynamic pictures of membrane pore formation. This project will combine various microscopy techniques to obtain structural and dynamic information of proteins during their assembly and insertion into the membrane at high spatial and temporal resolution.
It will combine the highly interdisciplinary and complementary expertise of 3 academic supervisors: in atomic force microscopy (Dr Bart Hoogenboom, www.london-nano.com/our-people/academics/bart-hoogenboom), in single-molecule fluorescence microscopy (Dr Alan Lowe, www.arlowe.co.uk), and in electron microscopy of pore forming proteins (Prof Helen Saibil, people.cryst.bbk.ac.uk/~ubcg16z/Site/Home.html), and build on current work in their research groups, in the framework of an on-going BBSRC grant awarded to Hoogenboom and Saibil.
By elucidating the mechanism of membrane pore formation by pore-forming proteins, we aim to create new opportunities for drug design and testing: e.g., the prevention of pore formation by pneumolysin would be a significant advance in the treatment of bacterial pneumonia; the ability to control the pore-forming activity of perforin in the human immune system could be an important means of regulating the immune response during and after tissue/organ transplantation or could alleviate the perforin-dependent cytotoxicity in autoimmune diabetes.