|Sophie Morse, Periklis Pantazis||Non-invasive manipulation and imaging of the brain’s immune system||Lab based||Biomechanics & mechanobiology, Biomedical sensing diagnostics & imaging, Neurotechnology & robotics||
Our brain has its own dedicated immune system and rapid response team: microglia. These cells actively survey the brain, clearing away toxins and pathogens. The ability to temporarily stimulate microglia has generated much excitement, due to its potential to treat brain diseases. For example, stimulating microglia can help clear away the amyloid-beta plaques that build up in Alzheimer’s disease.
Focused ultrasound is a non-invasive and targeted technology that can stimulate microglia in any region of the brain. However, how ultrasound is stimulating these crucially important cells is unknown.
This project aims to visualise whether focused ultrasound stimulates PIEZO1 mechanically sensitive ion channels in microglia to better understand the mechanism of this stimulation (expertise in Dr Morse’s group). A genetically-encoded fluorescent reporter based on PIEZO1, GenEPi, developed in Dr Pantazis’s group, will be used to visualise whether ultrasound is stimulating these ion channels, that play multiple roles in the activation of microglia.
The student will design a setup to simultaneously image the activity of PIEZO1 with confocal microscopy while performing ultrasound stimulation, which will be tested in a microglial cell line.
These results will provide invaluable insight into the mechanism of how focused ultrasound stimulates microglia, allowing ultrasound treatments to be optimised to achieve improved beneficial therapeutic effects for the treatment of neurological disorders, such as Alzheimer’s disease.
Applicants should be willing to work in an interdisciplinary environment and be open to learn new technologies.
Sophie Morse, James Choi
|Do immune cells enter the brain when delivering drugs across the blood-brain barrier with focused ultrasound?||Lab based||Molecular and cellular bioengineering||
Focused ultrasound and microbubbles is the only technique that can non-invasively, locally and temporarily open the blood-brain barrier to allow drugs into the brain. The way this technology works is by first injecting clinically-approved microbubbles and drugs into the bloodstream. When the microbubbles reach the area where the ultrasound is targeted in the brain, these bubbles oscillate, mechanically stimulating the blood vessels, allowing the barrier to open so that drugs can get reach the brain.
This technology has generated a lot of excitement as the blood-brain barrier currently prevents over 98% of drugs from entering the brain. Therefore, this technique can allow drugs that have previously failed clinical trials due to this barrier, to be tested again. But do immune cells also infiltrate from the blood into the brain, together with the drug, while the blood-brain barrier is open?
In some situations immune cell infiltration would want to be avoided, for safety reasons. However, in other cases, such as when treating brain tumours, the presence of peripheral immune cells inside tumours could really help. Our own immune cells are actually best suited at tackling the complex heterogeneity of brain tumours.
In this project, you will explore with sectioning, staining and fluorescence microscopy whether different types of immune cells are extravasating into the brain when the blood-brain barrier is opened with focused ultrasound. Ultimately, the aim is to find out with which ultrasound parameters you would get immune cells entering the brain, to either choose parameters for a safer drug delivery profile without immune cell presence, or to harness the power of our own immune cells to treat brain tumours.
Any immunology knowledge, tissue sectioning, immunohistochemical staining, or fluorescence microscopy experience would be useful but not necessary.
|Can focused ultrasound stimulate the activity of the brain’s innate immune cells?||Lab based||Biomedical sensing diagnostics & imaging, Molecular & cellular bioengineering, Neurotechnology & robotics||Microglia are the innate immune cells of our brain. They actively survey the brain and clear away toxins and pathogens. The ability to temporarily stimulate microglia has the potential to help treat brain diseases, such as brain tumours, Alzheimer’s disease and Parkinson’s disease. For example, stimulating microglia can help clear away amyloid-beta plaques that accumulate in Alzheimer’s disease brains.
Focused ultrasound is a non-invasive technique that has been used to stimulate neurons. However, we have discovered that microglia can also be affected depending on the way ultrasound is emitted. In this project, the level of microglia activation will be assessed for a variety of different ultrasound exposure parameters. Staining for various markers of microglia and their activation will be used to visualise changes in their morphology and activation level. Microscopy images will be assessed to explore what ultrasound can achieve in terms of microglial modulation with this non-invasive ultrasound technology.
|Can focused ultrasound stimulate astrocytes in our brain?||Lab based||Neurotechnology & robotics||
Astrocytes, together with endothelial cells, are the gatekeepers of the brain’s main security system – the blood-brain barrier. They control which substances enter and exit the brain, and keep harmful substances out. Astrocytes also regulate blood flow to transport nutrients to neurons depending on their energy needs. These cells are at the forefront of our thought processes: they regulate our synapses, and recycle and secrete neurotransmitters.
The ability to temporarily stimulate astrocytes has the potential to help treat brain diseases, such as Alzheimer’s disease and Parkinson’s disease. Focused ultrasound is a non-invasive and targeted technique that has been used to stimulate neurons. However, we have discovered that the activity of astrocytes can also be modulated depending on the way ultrasound is emitted.
In this project, the level of astrocyte activation will be assessed for a variety of different ultrasound exposure parameters. Staining for various markers of astrocytes and their activation will be used to visualise (with microscopy) changes in their morphology and activation level. This project will lead to key advances in the unexplored territory of how the activity of the brain’s gatekeepers can be non-invasively modulated with ultrasound to treat brain diseases.