Applications for entry to our Postgraduate (Research) Training Programme for Admission in Academic Year October 2018 – September 2019
Deadlines for applications for admission who wish to be considered for funding in the academic year October 2018 – September 2019 are as follows:
Gates US: 11th October 2017
Graduate Funding Competition: 6th December 2017
* IMPORTANT – this included applications from applicants who wish to be considered for Cambridge Trust funding (both inside and outside the EU).
***Please note that ALL supporting documents (references, transcript, CV) must be uploaded within 7 days of the date of applying***
Short listing meetings for applications will be first week of January 2018, followed by interviews 23rd, 24th & 25th January. Only those shortlisted for interviews will be contacted by e-mail.
Research projects for 2018/19
Research projects available (start dates: October 2018, January 2019, April 2019). Most supervisors will accept both PhD and MPhil (by Research) students. Please follow the instructions on the previous page (How to Apply).
We offer the following projects for 2018/19. Follow the links to find out more information about the supervisor and group, it is advisable to contact supervisors before applying. For more information about a specific project please contact the individual supervisor using the e-mail address provided, it is recommended that applicants contact supervisors prior to applying. However, please do not submit an application to the individual supervisor. All applications must be submitted following the process detailed on our ‘How to apply’ page
Professor Franklin Aigbirhio (firstname.lastname@example.org) – Wolfson Brain Imaging
- Synthesis and Evaluation of Novel PET Probes for Imaging Aggregated Protein Structures linked with Neurodegenerative Diseases
This project’s objective is to develop novel in vivo PET probes that are selective to protein aggregates, which are neuropathological features of various neurodegenerative diseases, including Alzheimer’s disease and frontotemperal dementia. The project would involve organic synthesis and in vitro assays of compounds, combined with developing the radiosynthesis of the novel PET probes. Evaluation of the probes would involve in vitro radiographic methods and in vivo imaging in models of dementia using a high resolution PET scanner.
- Development and Application of Novel PET Markers of Neuroinflammation
This project’s objective is to develop novel in vivo PET probes for application as sensitive markers of neuroinflammatory processes which are key components of several pathologies, including stroke, traumatic brain injury, multiple sclerosis and dementias. The project would involve organic synthesis and in vitro assays of compounds, combined with developing the radiosynthesis of the novel PET probes. Evaluation of the probes would involve in vitro radiographic methods and in vivo imaging in models of neuroinflammation using a high resolution PET scanner.
- Development of GSK-3 Radioligands
This project’s objective is to develop PET radioligands for the key enzyme Glycogen synthase kinase 3 (GSK-3) for which growing evidence shows it plays a pivotal and central role in the pathogenesis of several dementias. The project would involve organic synthesis and in vitro assays of compounds, combined with developing the radiosynthesis of the novel PET probes. Evaluation of the probes would involve in vitro radiographic methods and in vivo imaging in models of neurodegeneration using a high resolution PET scanner
NOTE: these projects are particularly suited to graduates in chemistry.
Ear Institute Hearing Related Projects:
- Developing New Tests for Site of Lesion in Hearing Loss (PhD only – suitable for clinical otology, audiology or auditory science backgrounds)
(co-supervisor Professor Brian Moore)
Hearing loss is often a black box, described by symptoms (such as sudden hearing loss) rather than the underlying biology. The aim of this project is to develop and apply newer and more sophisticated tests of auditory function tease out if the site of lesion is at the inner ear, synapse or auditory nerve.
This project will use and modify current tests in electrophysiology such as electrocochleography, ABR, and frequency following responses, and psychoacoustic tests such as amplitude modulated noise, reversed speech etc. in a series of patients with suspected or known pathologies in the cochlear basilar membrane mechanics, auditory nerve, synapse and outer hair cells to develop a panel of discriminatory tests that can pinpoint the site of pathology better in hearing impaired subjects.We will liaise with animal researchers using genetic knockout mice with known sites of pathophysiology to corroborate our findings in patients.
- Cochlear Implant Stimulation Spread in Patients and Models (PhD only – suitable for clinical otology, audiology or auditory science backgrounds)
(co-supervisor Dr. Bob Carlyon)
Cochlear implant results are severely impacted by current and stimulation spread inside the cochlea. This makes it very difficult to selectively stimulate different parts of the auditory nerve for to achieve frequency selectivity. This project will use sophisticated methods to interrogate the stimulus and response functions in-vivo in patients with implanted cochlear implants, to tease out those electrodes that are causing the most stimulation spread.
Simultaneously, the project will work on a cadaveric model with implanted cochlear implants and directly measure stimulation spread within the cochlea.
- Developing 3-D Reconstructed Models of the Human Auditory Nerve Processes in the Cochlea (MPhil – suitable for clinical otology, imaging, or anatomy backgrounds)
(co-supervisor Dr Matt Mason)
To truly understand current and electrical flows within the cochlea in patients with cochlear implants, we would like to model the implant and its relation to the auditory nerve cells in Rosenthal’s canal, as well as their peripheral and central processes in the cochlea. To do this requires a strong 3D understanding of the relative positions of these structures.
This project will use microCT scans of the cochlea, and possibly histology sections to segment and reconstruct the neuronal anatomy of the cochlea for human cochlea’s.
- Measuring Acoustic Sound Fields that Hearing-Impaired Subjects Function in (PhD or MPhil – suitable for engineering, acoustics, otology or audiology backgrounds)
(Co-supervisor Dr Anurag Agrawal)
As one of the largest auditory implant centres in the country, we have clinical experience with thousands of patients. Their hearing experience at home is often subjectively not well correlated with the very controlled tests of hearing function that we use clinically. A large missing piece is what kind of acoustic environments the patients have to function in their real daily lives.
In this project, we are developing a wearable body technology that uses sophisticated probes of the auditory/acoustic environment during the patients daily activities. These will be correlated with the patient’s subjective and objective measures of hearing difficulty and effort of listening, to develop more realistic programming parameters for patient functioning.
Vestibular and Balance Related Projects:
- Physiologic precursors to acute attacks in Meniere’s Disease (MPhil, suitable for otology, audiology or biochemistry backgrounds)
Meniere’s Disease is the triad of tinnitus, hearing loss and vertigo. It is a particularly disabling condition, with unpredictable episodes of incapacitating vertigo. Why these episodes cluster into particularly bad periods, and what body chemistry and other changes happen as precursors to these episodes is largely unknown. Many factors have been theorized to trigger acute attacks, particularly changes in body chemistry such as sodium levels and body fluid, environmental barometric pressure. One possible marker of the state of cochlear dilatation is the phase of optoacoustic emissions. This project will follow a group of Meniere’s Disease patients with daily logging of urine/saliva osmolality, urine/saliva electrolytes, specific gravity, body weight, bioimpedance measurements, barometric pressure and optoacoustic emission phase, along with tracking of vertigo episodes to try and determine the body chemistry elements that might contribute to clusters of acute attacks, and whether they can be acutely modified to abort the attacks.
- Point of Symptom Measurements in Patients with Vertiginous Disorders (PhD only, suitable for otology, audiology, engineering or biomechanics backgrounds)
Patients with vertiginous disorders often have symptoms at home, and when seen in the clinic are quiescent. This makes it difficult to understand the biologic changes during the episodes, and differentiate the various disorders. We are developing wearable technologies to measure aspects of eye movement, pulse, EEG and hearing during attacks. This project will take groups of patients with intermittent symptoms of imbalance or vertigo, and help develop and validate the wearable technologies to log the underlying physiology changes during attacks, as diagnostic aids and measures of therapeutic interventions.
Professor Roger Barker (email@example.com) – Neurology/ J v G Centre for Brain Repair
- Modelling the Dementia of Parkinson’s Disease (PhD only)
(Second Supervisor: Maria Grazia Spillantini)
While Parkinson’s disease (PD) is a well known, common disorder of movement control, it is less recognised as a risk factor for dementia. Indeed 10 years into the illness about 40% of patients have this complication which has devastating consequences on their quality of life. However, we currently have no way of treating this aspect of the disease outside some symptomatic therapies with cholinesterase inhibitors. This is part relates to a paucity of pre-clinical animal models of this condition. The project will involve developing a new rodent model of the dementia of Parkinson’s disease using selective lesions. The model will then be tested for behavioural deficits ahead of testing new therapeutic agents to prevent or reverse the deficits so generated.
- Rescuing Vulnerable Neurons in Parkinson’s Disease (PhD only)
(Co-supervised by Dr. Wei-Li Kuan)
Although being traditionally considered as a movement disorder that is pathologically defined by the loss of midbrain dopaminergic neurons, the fact that pathological alpha-synuclein can “propagate” in a stereotypic spatiotemporal pattern, and the presence of non-motor symptoms years before motor impairment, suggest that the pathogenesis of Parkinson’s disease (PD) is much more systemic, potentially involving both the central and peripheral nervous systems. Intriguingly, selective population of neurons are very resilient to alpha-synuclein toxicity, and appear to be less affected even at an advanced stage of disease. We have recently found that a systemic delivery of misfolded alpha-synuclein induces a highly selective neuropathology in nontransgenic animals resembling early stages PD. In particular there were progressive gastrointestinal and olfactory impairments with corresponding cellular deficits in selective subsets of neurons. Using a combination of cellular and molecular biology techniques, the objective of this PhD project is to study the mechanism(s) driving such selective vulnerability in different neuronal subsets, with an aim to identify novel targets to treat PD.
- Investigating the Immune Basis of Parkinson’s Disease (PhD only)
(Supervisors: Professor Roger Barker co-supervisor Dr Caroline Williams-Gray)
It is now well established that immune activation occurs in Parkinson’s disease, but its role in driving the disease process remains controversial, in particular whether it is a primary determinant of disease progression, or a secondary epiphenomena. This is a critical question to address given that the immune system is a tractable target for disease-modifying therapy. This project will investigate markers of immune activation and immunosenescence in blood and CSF samples from patients with both prodromal and early stage Parkinson’s disease to establish whether immune activation precedes disease onset and whether it is predictive of longitudinal disease progression rates. Techniques will include multiplex immunoassays, immunophenotyping using flow cytometry, new techniques such as CyTOFF (which allow labelling of large numbers of markers on a single cell), and functional lymphocyte and monocyte assays. This work will allow detailed characterisation of immune abnormalities in early PD to guide the development of future immune-based therapies and identify optimal immune-related biomarkers to track response to such therapies.
Dr Dennis Chan (firstname.lastname@example.org) Neurology
- Virtual Reality, 7T MRI and tau-PET studies of Entorhinal Cortex-Hippocampal Circuit involvement in Asymptomatic people at risk of Alzheimer’s Disease (PhD only)
(co-supervisors: Dr Su Li and Professor John O’Brien, Department of Psychiatry)
The entorhinal cortex (EC) and hippocampus are the first cortical regions to exhibit neurodegeneration in Alzheimer’s disease (AD) and emerging evidence suggests that tau pathology spreads trans-neuronally within the EC-hippocampal circuit before spreading to the neocortex. Detection of initial changes in EC-hippocampal function would therefore aid diagnosis of AD in its very first stages.
To test the hypothesis that EC and hippocampal function are impaired prior to symptom onset in people at risk of AD, this project will utilise knowledge of the roles of the EC and hippocampus in spatial navigation and memory. Immersive virtual reality-based tasks of path integration, object recognition and conjunctive object-location memory will be used to test respectively medial EC, lateral EC and hippocampal function in asymptomatic individuals aged 40-59 with risk factors for AD, recruited to the PREVENT study http://preventdementia.co.uk. Structural and molecular pathological correlates of the VR functional data will be obtained using ultra high resolution 7T MRI and tau-PET scanning respectively. This project will provide the successful applicant with a background in cognitive neuroscience and training in state of the art behavioural and neuroimaging analyses.
- Hippocampal Replay and Memory Consolidation in Alzheimer’s Disease (PhD only)
(co-supervisor: Dr Caswell Barry, University College London)
Newly encoded memories are consolidated during sleep and other periods of rest. In animal models, the reactivation of hippocampal neurons that were active during the initial memory encoding (hippocampal replay), is believed to provide the neural mechanism for consolidation. Presentation of sensory cues during memory encoding can improve consolidation if these cues are re-presented during post-encoding rest. Given that impaired consolidation contributes to the memory decline in Alzheimer’s disease (AD), cued memory reactivation during sleep might represent a means of improving memory in the early stages of disease before the onset of dementia.
- This will be investigated further in this translational project involving first stage hypothesis testing in preclinical models of AD and second stage application to people at risk of dementia. Years 1 and 2 will be spent in the lab of Dr Caswell Barry, University College London, with the following hypotheses to be tested:
Hippocampal replay is impaired in AD mice and is associated with impaired memory consolidation.
Sensory cueing and/or modulation of the cholinergic inputs to the hippocampus (using DREADDS to the medial septum) enhance replay and improves consolidation.
Year 3 will follow on from successful completion of Year 1-2 work and will be based in Cambridge under the supervision of Dr Chan. The outputs arising from the animal work will be used to test the hypothesis that cued reactivation improves consolidation of newly learned memories in people at risk of AD. The successful applicant will receive training in single cell recording in vivo as well as behavioural testing within a translational research environment.
- Use of Wearable Technologies to detect Alterations of Behaviour in People at risk of Alzheimer’s Disease (PhD only)
(co-supervisor: Professor Cecilia Mascolo, Department of Computer Science)
The aim of this project is to use apps based on wearable technologies, such as smartphones and smartwatches, to detect changes in functions that precede the onset of dementia, such as navigation and sleep. In collaboration with Cecilia Mascolo, Professor of Mobile Systems at the University of Cambridge, we have developed and piloted the use of several apps, and this project will involve implementation of these apps in cohorts at risk of AD, comparison of their diagnostic classification accuracy against currently used cognitive tests and app validation against established markers of disease such as MRI brain scanning. The successful student will be encouraged to investigate additional options for passive sensing of everyday behaviour.
Applicants with a background in programming or computer science would be particularly encouraged.
Professor Patrick Chinnery (email@example.com) – Neurology (PhD Only)
- Neurogenetics and Mitochondrial Disorders
Mitochondrial disorders are a major cause of inherited neurological disease affecting ~ 1 in 4000 of the population. Our work spans the whole translational spectrum, from basic science aimed at understanding mitochondrial biology and how it relates to human disease, through to clinical trials studying new treatments in patients. My ‘wet’ research laboratory is based on the MRC Mitochondrial Biology Unit (MBU) within the Cambridge Institute for Medical Research (CIMR) building. We use whole genome and transcriptome sequencing to discover new mitochondrial disorders, we study the disease mechanisms in cell and animal models to understand how mutations cause specific patterns of disease, and we carry our deep-phenotyping studies on patient cohorts, using this information to guide experimental medicine and early phase clinical trials. My group offers both clinical and basic science PhD students the opportunity to work in all of these areas. Specific examples include:
- Discovering New Neurogenetic Diseases
We play a leading role in the Genomics England – Neurology Genomics Clinical Interpretation Partnership. This involves the analysis of data from the 100,000 genomes project which included >500 patients with new neurogenetic diseases. A PhD student working in this area would develop computational and bioinformatic skills to allow the interrogation of whole genome and transcriptome data sets. New candidate genes will be validated by segregation analysis, leading to functional validation of the most promising new genes in cell models of disease. Non-clinical students would have the opportunity to work in collaboration with investigators at the MRC Mitochondrial Biology Unit to define new disease mechanisms using state-of-the-art cell and animal models, including induced pleuripotent stem cells. Clinical students would have the opportunity to describe the deep phenotype and natural history of these disorders for the first time using world-leading imaging and experimental medicine facilities on the Biomedical Campus.
- The Inheritance of Mitochondrial DNA Diseases
(Collaboration with Prof Azim Surani, Gurdon Institute)
Mutations of mitochondrial DNA (mtDNA) are a major cause of human disease. Many are heteroplasmic, with a mixture of mutated and wild-type genomes. Differences in the proportion of heteroplasmy determine the severity of disease, but the mechanisms responsible for the differences are poorly understood. We have previously shown that a drastic reduction in the mount of mtDNA occurs during germ cell development, leading to a genetic bottleneck effect. However, there also appears to be evidence of selection against deleterious mutations, ‘purifying’ the germ line. The precise mechanisms are not understood, but are of fundamental importance to the development of new techniques to prevent the transmission of mtDNA diseases. Our preliminary data implicates the ‘oxidative switch’ during germ cell migration and proliferation. The aim of this project is to define when and how this switch leads to the suppression of pathogenic mtDNA mutations within germ cells, opening new avenues for preventative therapies.
Stewart JB, Chinnery PF. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nature Reviews Genetics 2015 Aug 18;16(9):530-42. doi: 10.1038/nrg3966. PMID:26281784
Tang WWC, Dietmann S, Irie N, Leitch HG, Floros VI, Hackett JA, Chinnery PF, Surani MA. A Unique Gene Regulatory Network of the Human Germline Resets the Epigenome for Development. Cell 2015;161(6):1453-67. PMID:26046444
Taylor RW, Pyle A, Griffin H, Blakely EL, Duff J, He L, Smertenko T, Alston CL, Neeve VC, Best A, Yarham JW, Kirschner J, Schara U, Talim B, Topaloglu H, Baric I, Holinski-Feder E, Abicht A, Czermin B, Kleinle S, Morris AAM, Vassallo G, Gorman G, Ramesh V, Turnbull DM, Santibanez-Koref M, McFarland R, Horvath R, Chinnery PF. Use of whole exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiency. Journal of the American Medical Association 2014;312(1):68-77. PMID:25058219
Freyer C, Cree LM, Mourier A, Stewart JB, Koolmeister C, Milenkovic D, Wai T, Floros V, Hagström E, Chatzidaki EE, Wiesner R, Samuels DC, Larsson N-G, Chinnery PF. Variation in germ line mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. Nature Genetics 2012;44(11):1282-5. PMID:23042113
Professor Michael Coleman (firstname.lastname@example.org) – J v G Centre for Brain Repair
- Developing an Organotypic Slice Culture Model for sporadic Alzheimer’s Disease
(Second supervisor – Professor Giovanna Mallucci)
Using tissue from transgenic mice expressing a mutant form of amyloid precursor protein, we have developed a model of familial Alzheimer’s disease in organotypic hippocampal slice cultures (Harwell & Coleman, Molecular Neurodegeneration, 2016). These cultures show high levels of amyloid beta peptide (Abeta) and loss of synapses and they have the advantages of allowing convenient monitoring of the extracellular medium and easy delivery of exogenous molecules to probe mechanism and test therapeutics. However, the large majority of Alzheimer’s disease cases are sporadic and associated with risk factors such as inflammation, diabetes, vascular impairment, etc rather than APP or presenilin mutation. This project will mimic these risk factors in slice cultures from wild-type mice to identify conditions that raise Abeta generation and any associated synapse loss. We will then probe the mechanisms by which these changes arise. We will also model the greatly increased risk in Down’s syndrome using modest increases in wild-type APP and other relevant genes found on human chromosome 21. These studies will improve understanding of pathogenic mechanisms of Alzheimer’s disease in the large majority of cases that do not involve coding mutations.
- Genes Regulating Axon Degeneration as Risk Factors for Human Neurodegenerative Disease
(Second supervisor – Professor Keith Martin)
The aim of this study is to understand why axonal damage secondary to causes such as diabetes, glaucoma, inflammation and traumatic brain injury is more profound in some people than in others, even when severity of the primary cause is closely matched. We will study candidate genes known to control a well-characterised molecular pathway of axon degeneration, Wallerian degeneration. Animal studies have confirmed this pathway influences axon vulnerability, while human GWAS and exome studies have linked Wallerian degeneration to some specific human neurodegenerative diseases such as ALS and peripheral neuropathy (Conforti et al, Nat Rev Neurosci 2014). However, a full understanding of its role in human disease requires hypothesis-driven investigation in humans. The study has two complementary sections. In a phenotype-led part we will study genes from the Wallerian pathway in individuals with well-matched primary conditions (diabetes, inflammation, etc.) but very different outcomes for axon survival. A parallel, genotype-led study will use gene editing to introduce polymorphisms from these genes known to occur in the human population into human iPS-derived neurons and test the effects on axon survival. This work builds on a rapidly improving understanding of the molecular mechanisms of Wallerian degeneration to pave the way for clinical application of this knowledge.
Professor Marek Czosnyka (email@example.com ) – Neurosurgery
- Mathematical Modelling of Brain Haemodynamics and Pressure-Volume Compensation
Dynamical properties of cerebral blood flow (CBF) and cerebrospinal fluid circulation (CSF) can be modelled by a structure of nonlinear differential equations (1). Models describe such phenomena as autoregulation of blood flow, brain venous blood outflow, compensatory role of CSF circulation, etc (2). They are relevant to understanding of pathophysiological mechanisms after traumatic brain injury, subarachnoid haemorrhage, stroke, in hydrocephalus and in idiopathic intracranial hypertension. Database of recorded clinical signals is available for verification or identification of successful modelling structures. Project will be focused on further refinement of the existing models, including their application for non-invasive assessment of intracranial pressure (3), asymmetry of CBF and phenomenon related to collapse of cerebral venous sinuses. Project suits neuroscientists with strong computer skills (including writing own codes, advanced Matlab, etc). Further readings (4). 1. Czosnyka et al. J Neurol Neurosurg Psychiatry. 1997 Dec;63(6):721-31. 2. Piechnik et al. J Cereb Blood Flow Metab. 2001 Feb;21(2):182-92. 3 Kashif FM et al. Sci Transl Med. 2012;4(129):129ra44. 4.http://www.neurosurg.cam.ac.uk/pages/brainphys/index.php
- Methodology of Clinical Tests for Assessment of Cerebral Autoregulation after Traumatic Head Injury
Various methods exist for assessment of autoregulation of Cerebral Blood Flow (CBF). They incorporate different modalities: arterial blood pressure, intracranial pressure, blood flow velocity, cerebral perfusion pressure, and brain tissue oxygenation (1). Dynamical tests of cerebral autoregulation include time series analysis, analysis of models based on transfer function, wavelet decomposition, non-linear decomposition, etc. The aim of the project is to compare various methodologies, various modalities and compare them from the point of view of clinical utility in a group of head injured patients. Strong emphasis will be put on feasibility studies of new and existing methodologies at the bedside: such as a concept of ‘optimal’ Cerebral Perfusion Pressure or individualized threshold of intracranial pressure. Also links between brain physics modalities and electrophysiology and biochemistry will be of interest Project is ideal for a person having medical or biological background with strong practical computer skills. Further readings (4). 1. Czosnyka M et al. Neurocrit Care. 2009;10(3):373-86. 2. Aries MJ et al. Crit Care Med. 2012; 40(8):2456-63. 3. Lazaridis C et al. J Neurosurg. 2014 Apr;120(4):893-900. 4.http://www.neurosurg.cam.ac.uk/pages/brainphys/index.php
- Mechanisms controlling Cerebrospinal Fluid dynamics
In various pathologies, reasons for intracranial hypertension may be different. In hydrocephalus: disturbed outflow of Cerebrospinal Fluid (CSF); in idiopathic intracranial hypertension (IIH): obstruction of venous blood outflow; in head injury and stroke: brain edema, increased vasogenic component of ICP, failing regulation of cerebral blood volume or all three factors together, etc. (1) This is an interdisciplinary project requiring good background in clinical neurosciences, brain physics and computational methods (time series analysis, dynamic modelling). Clinical applications are envisaged (but not limited to) mainly in area of hydrocephalus (2) and IIH . Vast database of recorded signals and clinical material (over 5000 cases) can be used for mastering new methodologies of processing and modelling (3). Strong knowledge of brain imaging techniques will be essential. Project is ideal for a person having medical or biological background with strong practical computer skills. Further readings (4). 1. Czosnyka M, Pickard JD. J Neurol Neurosurg Psychiatry. 2004;75(6):813-21. 2. Weerakkody RA et al. Acta Neurol Scand. 2011;124(2):85-98. 3. Varsos GV et al.
Professor Robin Franklin (firstname.lastname@example.org) – Stem Cell Neurobiology/WT-MRC Cambridge Stem Cell Institute
The regenerative biology of adult CNS stem cells. In my laboratory our main area of research is aimed at understanding how adult CNS stem cells respond to injury and contribute to regeneration, chiefly the regeneration of new myelin sheaths – or remyelination (and area in which we are considered world leaders). Our lab is primarily a cell biology laboratory, pursing the underlying mechanisms on which future developments in therapy are based. Many of the projects are undertaken in collaboration with my colleague Dr. Chao Zhao.
There are many projects ongoing and available as PhD projects and precisely what form a project might take is very fluid. This is open to discussion with potential PhD students. Example of the sorts of projects available are as follows:
- Rejuvenating Ageing CNS Stem Cells by Partial Reprogramming
Therapeutic enhancement of remyelination is likely to be a highly effective means of preventing much of the axon loss that underpins the progressive phase of MS. Remyelination efficiency declines with ageing. This means that the need for remyelination therapies increases with disease progression. It may also imply that adult OPCs, the cells primarily responsible for remyelination, become refractory to such therapies with increasing age. We have generated data from ageing OPCs showing that this is indeed the case. Thus, in order to make endogenous adult OPCs in the ageing CNS more responsive to remyelination-enhancing therapies it may be necessary for them to be rejuvenated. New and exciting evidence shows that partial reprogramming can rejuvenate ageing cells and improve regeneration of ageing pancreas and skeletal muscle (Ocampo et al ., Cell 2016). In this project will be apply this approach to the problem of ageing adult OPCs and the age-associated decline in remyelination efficiency. The project is designed to be achievable by a committed PhD student.
- Adult Brain stem Cells, Ageing and Circadian Rhythms
This project concerns the cell biology of adult stem cell ageing, an especially ‘hot topic’ in current stem cell research. An area of current interest is how the biology of circadian rhythms controls the maintenance and properties of adult CNS stem cells and how disturbances in these rhythms with ageing can disrupt normal regenerative processes. We address questions of fundamental stem cell biology that underpin our understanding of disease and are needed to therapeutically harness the immense regenerative potential latent within the aging CNS.
- Do Ageing CNS Progenitors become Vulnerable to Autoimmune Damage with Disease Progression in Multiple Sclerosis?
The project has arisen from unpublished data generated during this collaboration, where, by proteomic analysis of CNS progenitors, we have discovered that as adult progenitors age they acquire expression of antigens known to be targets of the autoimmune process in MS. This raises the exciting and potentially transformative hypothesis that one of the reasons why the regenerative process of remyelination fail in MS is because the cells primarily responsible for remyelination themselves become vulnerable to destruction by the maladaptive immune process of the disease.
- What Role does Angiogenesis play in Remyelination and How does this Change within Ageing?
Given the central role of angiogenesis in many regenerative processes it is somewhat surprising that this has not been fully explored in the context of CNS remyelination. This project will first examine the role of angiogenesis using experimental approaches, and then use the information derived to analyse and interpret data obtained from MS tissue. It will use both in vitro approaches and experimental in vivo models of demyelination/remyelination to explore cross-talk between endothelial and oligodendrocyte lineage cells, the mechanisms within a remyelinating lesion that govern angiogenesis, and how these change with ageing.
Dr Andras Lakatos (email@example.com) – J v G Centre for Brain Repair/Neurology (PhD & MPhil)
My laboratory is focussing on regulators of complex transcriptional networks and novel signalling pathways in astrocyte-neuron-synapse interactions in physiology and neurological disease. In particular, this project is aimed at elucidating novel non-cell autonomous mechanisms in neurodegenerative diseases, such as Motor Neuron Disease (MND/ALS). We use both mouse models and patient derived human induced pluripotent stem cell (hiPSC) systems in combination with computational biological models to explore astrocyte mediated damage or recovery of the neuronal network. Our translational systems also offer an opportunity for testing potential therapeutic candidates in hiPSC models of neurodegeneration. The PhD or MPhil student will develop a broad spectrum of cell and molecular biology repertoire, in vivo techniques at the John van Geest Centre for Brain Repair and may also spend a part of their studentship in one of my collaborators’ laboratories (Dr R. Patani, Crick Institute and UCL; Dr C. Sibley, Imperial College and Prof. B. Khakh, UCLA). Another one-year MPhil project may be offered to an applicant with interest in computational modelling of astrocyte-neuronal networks, which is a joint project with Dr M. Lengyel (Department of Engineering, Cambridge). The latter may be more suitable for students with a background in computational biology, physics or engineering.
References:Tyzack, G.E., Sitnikov, S., Barson, D., Lau, N., Adams-Carr, K., Kwok, J.C., Zhao, C., Franklin, R.J., Karadottir, R.T., Fawcett, J.W. & Lakatos, A. Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression (2014). Nature communications 5:4294
Tyzack, G.E., Lakatos, A. & Patani, R. Human pluripotent stem cell-derived astrocytes: specification, characterization and relevance for neurological disorders (2016). Current Stem Cell Reports (Springer-Nature) 1-12
- Applying whole Genome Sequencing to Identify Novel Causes of Small Vessel Disease Stroke – (PhD only)
(Supervisor: Professor Hugh Markus)
Disease of the small blood vessels in the brain (SVD) accounts for 20% of all strokes and is the most common cause of vascular dementia. It also represents the most common type of stroke caused by familial or monogenic conditions. The most common of these is CADASIL but recently an increasing number of other monogenic forms of small vessel disease have been described. The ability to investigate this area has been transformed by whole genome sequencing technology. This is allowing us to understand for the first time how common these causes of stroke are, and to identify new monogenic forms of SVD. We are leading a UK wide project applying this technology to patients with suspected familial SVD as part of the BRIDGE project and 100,000 Genomes project. The student will work on data acquired in these initiatives. The project brings together a multidisciplinary team of clinicians involved in phenotyping and describing and clinical profiles, imagers who perform MRI brain imaging to understand disease pathogenesis, and statisticians who analyse the genetic data. The student would work in one or more of these areas.
Tan R, Traylor M, Rutten-Jacobs L, Markus H. New insights into mechanisms of small vessel disease stroke from genetics. Clin Sci (Lond). 2017 1;131:515-531. Tan RY, Markus HS. Monogenic causes of stroke: now and the future. J Neurol.
- Generation of a Human in-vitro Model for Large-Vessel Ischemic Stroke using Induced Pluripotent Stem Cell (iPSC)
(Supervisor: Hugh Markus co-supervisor Alessandra Granata)
We are using human induced pluripotent stem cells (iPSC) to generate a vascular model of ischaemic large-vessel stroke. A genome-wide stroke association study (GWAS) lead by Professor Markus has identified a genetic variant in the enhancer region of the Histone Deacetylase 9 Gene (HDAC9) as the strongest risk locus for large-vessel stroke to date1. This stroke-associated variant appears to increase HDAC9 expression, which could potentially affect the genetic and epigenetic landscape of the vascular cells of the large arteries of the brain, where the gene is highly expressed.
We are aiming to use iPSC line carrying the HDAC9 stroke-associated variant to:
- Investigate how the variant influences HDAC9 regulation and which transcriptional factors are involved in controlling the enhancer region.
- Correct the variant using CRISPR-Cas9 gene-editing approach to generate an isogenic line.
- Differentiate the iPSC mutant and CRIPSR-corrected lines into the vascular cells of the vessel wall, including smooth muscle (SMC) and endothelial cells (EC) using well-established protocols2,3 to mimic stroke phenotype.
- Characterise the iPSC-derived SMC and EC phenotypic changes caused by the HDAC9 stroke-variant and perform a transcriptomic analysis to identify new target(s), which could lead to the development of new effective therapies for stroke.1) Bellenguez, C. et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat. Genet. 44, 328–33 (2012).2) Cheung, C., Bernardo, A. S., Trotter, M. W. B., Pedersen, R. A. & Sinha, S. Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility. Nat. Biotechnol. 30, 165–73 (2012).3) Patsch, C. et al. Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells. Nat. Cell Biol. 17, 994–1003 (2015).
- Analysis of Brain Networks using MRI in patients with Cerebral Small Vessel Disease
(Supervisors: Professor Hugh Markus and Dan Tozer)
Cerebral Small Vessel Disease (SVD) is a common condition affecting older people in which disease of the small perforating vessels in the brain results in both small strokes and cognitive decline. Our current understanding is that damage to the white matter tracks within the brain results in disruption of complex circuits linking the cortex and sub-cortex, disrupting brain networks and therefore resulting in cognitive impairment.
It is possible to gain information about these networks using MRI techniques. Diffusion Tensor Sequences (DTI) can be used to construct structural brain networks. Functional MRI (fMRI) sequences can be used to derive functional networks, particularly in the resting state (i.e. no task driven activation). In recent data we have shown that the degree of network disruption, of structural networks, is a strong predictor of cognitive decline (Lawrence et al. Neurology, 2014;83:304-311).
Network analysis and graph theory have recently become popular methods in neuroimaging with connectivity of brain regions being measured and alterations in many diseases being seen. These exciting methods are still undergoing development and there are still many unanswered questions as to the best way to analyse the data.
This project will involve refinement and development of methods used for network analysis. Using recently acquired data the reliability of the different network measures will be determined, for example the effect of using probabilistic, as opposed to deterministic tractography algorithms will be investigated. Different ways of analysing the networks will also be explored. The project will involve analysis of both structural and functional networks. In addition the effect of different brain pathologies imaged on MRI (such as white matter lesions and lacuna infarcts) on network function and derivation will be determined.
The project would suit a student with a keen interest in Neuroscience who could come from a science or mathematical/physics background. It will involve detailed MR image analysis so good computer skills are essential.
- How do Genes Interact with Today’s Environment in The Pathogenesis of Cerebral Small Vessel Disease? (PhD only)
(Supervisors: Professor Hugh Markus, co-supervisor Matthew Traylor)
Cerebral Small Vessel Disease (SVD) is the pathology underlying around a quarter of strokes, as well as being the major cause of vascular dementia. Despite its public health impact, we still know relatively little about mechanisms underlying the disease. However, recent genomewide association studies have begun to uncover the genetic variation that underlies the disease, with around a dozen loci now implicated. With genetic datasets rapidly expanding over the next few years, now is an exciting time in SVD and we hope to understand much more about the disease in the coming years.
A major gap in our understanding of the pathogenesis of SVD is how the modern environment interacts with these genetic factors to increase risk. Hypertension and Diabetes are major risk factors for SVD, but how these risk factors relate to genetic factors remains unclear. Whether factors such as smoking, physical activity and diet associate with SVD also remains unclear from the epidemiological data available. Until now, sufficiently large datasets to investigate these relationships in detail have not been available and many question remain. The advent of Mendelian Randomization also means that we have now have the ability to test causal relationships between risk factors and SVD, which opens up many avenues to explore these issues [Davey Smith et al; Hum Mol Genet 2015:23:R89-98].
Key questions include:
- Do particular genetic variants interact with lifestyle factors to increase risk of SVD?
- Do people with high genetic risk of SVD and poor lifestyle have significantly higher risk?Which lifestyle factors are causal for SVD?
- The focus of this project will be to interrogate, using MRI, lifestyle and genetic data from up to 100,000 participants from UK Biobank, how lifestyle and genetic factors confer risk of SVD, answering the key questions above. The student will carry out a series of studies to investigate these questions. A variety of methods, including Mendelian randomization, tests of gene-environment (GxE) interactions, and genome-wide interaction studies, will be used. Much of the work will be performed using statistical packages such as R, or software in a unix environment. Candidates should therefore have good computer literacy, or a willingness to learn.
Professor Keith Martin (firstname.lastname@example.org) – J v G Centre for Brain Repair / Ophthalmology
Our work aims to understand the mechanisms of retinal ganglion cell death in glaucoma and optic nerve diseases, and to develop new treatments using gene therapy, stem cells and other approaches. We also work closely with Quethera, a local biotech company co-founded by Keith Martin, to develop gene therapy approaches for glaucoma and other diseases. Work in the laboratory is constantly evolving and so available projects tend to change over time, but some examples are given below. PhD students are preferred but MPhil projects may be available in exceptional circumstances.
- Project 1: Can a BDNF/TrkB Receptor Gene Therapy Protect against Retinal Degeneration caused by a variety of Gene Mutations found in a variety of Orphan Inherited Eye Diseases?
(co-supervised with Prof James Fawcett)
Background: There are a number of rare inherited eye conditions which result from mutations within single genes responsible for normal cell metabolism and signalling that cause sight deterioration and blindness over time. Due to the limited numbers of subjects with these conditions, classical small medicinal molecule and recombinant protein drug discovery efforts to treat the small populations would not be economically viable for industrial research. However, gene therapies which can introduce gene sequences which code for the ‘normal’ functional proteins offer an exciting and promising approach to treating these conditions. However, for each rare condition, a specific gene therapy product would need to be designed, manufactured and tested in animal models and small clinical trials. Whilst this may be a viable approach for some conditions in which the orphan disease is more commonly encountered, for extremely rare mutations resulting in progressive blindness, even small scale targeted gene therapies would not be viable. For example, there have been shown to be around 50 genetic mutations responsible for a retinitis pigmentosa which results in initial poor night vision which may gradually progresses to complete loss in vision over time. Moreover, some of the mutations which result in the eye conditions are found in very large genes which would be technically very challenging to accommodate in a viral vector gene therapy product capable of targeting particular retinal target cell types. What is needed is a ‘ubiquitous’ retinal cell neuroprotective gene therapy which is capable of preventing retinal cell degeneration caused by a variety of genetic metabolic and signalling defects. We, together with the biotechnology company Quethera, have recently designed a novel gene therapy which can boost activity through the neuroprotective brain-derived neurotrophic factor (BDNF)/TrkB receptor pathway. This gene therapy is currently being progressed into clinical trials for the treatment of progressive glaucoma as it has been shown to be highly effective in preventing retinal ganglion cell death following a variety of pathophysiological insults. Due to the ability of the BDNF/TrkB gene therapy to up-regulate the generic anti-apoptotic cell survival pathway, this novel therapy may have utility in preventing other retinal cells from damage caused by different mutations.
The project: This is a project which will examine the ability of the BDNF/TrkB gene therapy to protect retinal structures in various transgenic mouse models of rare orphan diseases. The student will learn how to administer small volumes of gene therapy to the eye using intravitreal and subretinal injection techniques and to examine for efficient and long-term transgene expression in target retinal cells using immunohistochemical techniques. In some circumstances retinal cells do not normally degenerate in some of the transgenic mouse models maintained in standard laboratory housing (for example shaker-1 and abca-4 knockout mice models of Usher-1B syndrome and Stargardt disease, respectively) unlike in humans. However, human-like pathophysiology and retinal cell death can be induced when exposing animals to normal (bright) light. The student will learn to work with and improve animal models of rare inherited eye conditions so that the pathophysiology more closely resembles the human ophthalmic condition. Retinal structure and visual function will be assessed using confocal microscopy and electrophysiological techniques. A number of mouse transgenic models are currently commercially available and so the student has a high probability of generating exciting data which may indicate that the gene therapy be considered for clinical testing in a broader range of eye diseases than is currently planned.
- Project 2: Design of a Novel Gene Therapy Construct Capable of Facilitating Neuronal Axon Repair and Regeneration Following Injury
(co-supervised with Prof James Fawcett)
Background: Mature CNS neurons cannot normally regenerate their axons but the pathways preventing repair are being gradually uncovered. Attempts to induce axonal sprouting and regeneration by gene therapy in the Fawcett laboratory have shown promising results using vectors carrying large genetic cargos coding for transmembrane signalling integrins and intracellular signalling proteins such as the kindlin-1. However, effective targeting of neurons with mixtures of viral vectors, in the hope that cells will be transfected by each of the different vector subtypes, is unpredictable. Moreover, use of vector mixtures to deliver multiple large genes to target neurones is further complicated by reports that transgene expression will be gradually curtained by cells which recognise multiple promoter-driven systems as toxic. Long-term and maximal neuronal targeting could be better achieved using a single vector construct but this must be able to carry all the essential coding regions. The recombinant adeno-associated viral (rAAV) vector is the most widely used technology to target neurones but has a total genetic cargo limited to only 4.7 kilobases. Therefore, it will require significant efforts to design a genetic construct capable of stimulating the intracellular signalling pathways necessary for axonal regrowth and to overcome the extracellular negative influences of the PNNs.
The project: The aim of the programme will be to discover a way to accommodate only essential protein sequences required for axonal regeneration within a single vector construct and which is activated by a single promoter sequence. The construct must also overcome the negative influences of the PNNs to maximise attempts at axonal regeneration. Working closely with the biotechnology company, Quethera, we have recently designed and patented a novel gene therapy aimed at preventing retinal ganglion cell death for use in patients with advancing glaucoma and which contains multiple coding sequences for multiple therapeutic proteins, and controlled by a single promoter. Prototype vector constructs have already been designed and which will require testing prior to constructs refinement. The student will initially test DNA plasmid construct using in vitro cell-based assays to examine for expression and intracellular processing of the therapeutic proteins by Western blot and immunohistochemical techniques. As the DNA plasmid designs become more efficacious, constructs will be incorporated into viral vectors for use in animal models of axon degeneration, such as dorsal root ganglion axonal regeneration and optic nerve regeneration following axotomy or nerve crush damage. This is an exciting programme of work which aims to generate novel (patentable) genomic constructs which will may be considered for eventual use in humans.
- Development of a Novel Gene Therapy to Facilitate Axonal Repair and Regeneration after Optic Nerve Injury
BACKGROUND: Quethera is a Babraham-based advanced medicines company co-founded by Prof. Keith Martin, University of Cambridge. Quethera works closely with the Department of Clinical Neurosciences to develop new treatments for common diseases where gene therapy offers significant advantages over conventional medicines. Quethera’s first product is a gene therapy for glaucoma patients with worsening vision despite conventional treatment, a high unmet medical need. To add to their portfolio, Quethera aims to develop a therapy to improve neuronal repair and regeneration after injury. Mature CNS neurons cannot normally regenerate. Attempts to induce axonal regeneration by gene therapy in the Martin/Fawcett laboratories have shown promising results using vectors carrying large genetic cargos coding for transmembrane signalling integrins and intracellular signalling proteins such as the kindlin-1. However, effective targeting of neurons with mixtures of viral vectors is unpredictable and inefficient.
AIMS: This project offers an exciting introduction to advanced medicine R&D while working within a university environment on a programme which is at an early stage of development. The aim is to discover how to accommodate only essential protein sequences required for axonal regeneration in a single vector construct activated by a single promoter sequence. Prototype vector constructs have already been designed for testing and refinement by the student.
METHODS: You will learn techniques necessary for a biomedical career, including cell culture, immunohistochemistry, confocal microscopy, DNA plasmid design, viral vector construction and eye surgery. You will test DNA plasmid constructs in vitro for expression and intracellular processing of the therapeutic proteins. Constructs will be incorporated into viral vectors for use in animal models of axon degeneration. You will also learn to identify potential intellectual property, patent and regulatory processes and how new therapies are advanced towards the clinic.
SIGNIFICANCE: This project addresses a key translational challenge in regenerative medicine, aiming to improve optic nerve regeneration after injury. We believe this is an exciting project for a highly motivated individual who is keen to learn key laboratory research skills in preparation for a career either in academia or in the industrial advanced therapeutics arena which is set to grow significantly in the UK over the next decade.
Quethera, founded by Dr Peter Widdowson and Prof Keith Martin, is a biotech company based at Babraham Research Campus developing novel gene therapies for common diseases. Dr Widdowson has many years of experience in large pharmaceutical and biotech company R&D management and has already progressed several gene therapies for eye and brain conditions to advanced clinical trials. Prof Keith Martin is a clinician scientist ophthalmologist with a longstanding interest in gene therapy for the treatment of optic neuropathies; he was first to demonstrate that a rAAV gene therapy could reduce vision loss in models of glaucoma. Quethera is currently advancing its novel glaucoma gene therapy product into regulatory safety studies and towards clinical evaluation. Quethera has been showcased at the House of Lords and the London Stock Exchange, was a Runner Up in the Government’s BioStart Synthetic Biology Competition 2017, and has been hailed as a leading start-up company within the UK’s Advanced Medicines company portfolio. Quethera was also Highly Commended in the Cambridge Entrpreneurial Science and Technology Awards 2017.
Unlike many other gene therapy companies which focus on rare inherited diseases, Quethera’s product concepts target multiple pathophysiological pathways associated with common diseases that do not involve a single gene defect. Quethera’s therapies aim to provide significantly more efficacy as compared to treatments focusing on a single pharmacological site. However, gene therapies are often limited by the cargo capacities of viral vectors, reducing the potential to introduce multiple therapeutic genes. Quethera has overcome these problems with a novel genomic platform which allow multiple therapeutic genes to be accommodated within rAAV vectors, with gene expression being highly regulated by a single promoter. The Quethera approach aims to revolutionise the treatment of diseases exhibiting complex pathophysiology’s using therapies which require a single administration to target multiple therapeutic pathways.
Dr Will McEwan (email@example.com) – Clinical Neurosciences
- How do Pathological Protein Aggregates Enter the Cytoplasm?
Several neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are thought to be driven by the ‘seeded’ aggregation of cytoplasmic proteins such as tau and alpha-synuclein. This is a process that shares similarities with viral and prion infection, wherein a seed of highly structured aggregated protein promotes the conversion of native protein to the aggregated state. Our group is dedicated to understanding how such protein conformations propagate and developing new methods for therapeutically targeting propagation. In order for seeding to occur, aggregated proteins must transit cell-limiting membranes to gain access to the cytoplasm to contact pools of native protein. This is akin to the entry of viruses to the cytoplasm. However, unlike viral entry, very little is known about how protein seeds enter the cell.
A confounding problem in studying this process is accurately distinguishing cytoplasmic aggregates from extracellular and vesicle-resident aggregates. We will adapt techniques that originate from the field of virology to develop novel and highly sensitive methods for positively identifying cytoplasmic assemblies. We will perform experiments in physiologically relevant settings including cultured neurons to ask how entry occurs and which factors influence it. In particular, it is becoming clear that many known genetic risk factors in AD and PD code for proteins that are involved in endocytosis or vesicular function. We will investigate whether these proteins impact the entry of protein assemblies to the cytosol, potentially explaining their etiological role. An understanding of how entry of proteins seeds occurs and the factors that regulate it will be an important step in determining the molecular basis of neurodegeneration.
We are looking for students with a strong biological or medical background to carry out this research. You will become experienced in several techniques including cultured cell assays, confocal and other form of light microscopy, recombinant protein production and biophysical techniques.
Professor David Menon (firstname.lastname@example.org)- Division of Anaesthesia
- Longitudinal changes in traumatic brain injury (TBI) detected using MRI.
TBI is not a single insult with monophasic resolution, but a chronic disease, with dynamic processes that remain active for years. We will use data from the 5400 patient CENTER-TBI study (www.center-tbi.eu) to assess patient trajectories over the entire disease narrative, from ictus to late outcome, and correlate this with the functional outcome of patients including neurocognitive change.
- qCT for diagnosis, prognosis and treatment stratification in traumatic brain injury (TBI).
Current methods of CT classification in TBI are crude, time consuming, and provide an incomplete description of more subtle injury such as traumatic axonal injury and brain oedema. Better use of CT (including analysis absolute intensities, textural properties and temporal changes – collectively labelled Quantitative CT; qCT) may provide improvements. Automated methods will be developed, in conjunction with the Computer Vision group at Imperial College, for lesion detection, and measurement of clinical biomarkers, and will be used in conjunction with prognostic modelling being developed on the 5400 patient CENTER-TBI dataset (www.center-tbi.eu)
- The utility of MRI in mild traumatic brain injury (mTBI).
Despite a normal CT, up to one third of patients with mTBI may develop a persistent post-concussion syndrome. Conventional MR may detect more lesions but correlates poorly with outcome. This project will use more advanced methods, including diffusion tensor imaging and restating state fMRI, to better characterize the patients and determine those at most risk of persistent problems. Studies will be undertaken in the 5400 patient CENTER-TBI dataset (www.center-tbi.eu).
Dr Stefano Pluchino (spp24.cam.ac.uk) – Neurology
- Making Human iNSCs from People with Progressive MS (PwPMS)
(co-supervised with Luca Peruzzotti-Jametti)
This project will involve the development of stably expandable, forward programmed neural stem cells (NSCs) from People with progressive MS (PwPMS). Somatic cells will be reprogrammed to stably expandable directly induced neural stem cells (iNSCs) and then differentiated and monitored for several markers of pluripotency/multipotency, checked for morphological, function and genomic stability as well as senescence over time period in vitro. This project will highlight potential issues of stability and suggest methods of mitigating these, should they arise.
The long-term goal of this investigation will be to evaluate the safety of iNSCs for use in a first-in-men clinical trial, which is being organised at Cambridge. The final objective of this investigation is the determination of whether or not the therapeutic use of iNSCs in PwPMS can be taken forward into clinical trials.
- In Vivo Characterization and Manipulation of Succinate Dependent Injury in Neuroinflammation
(co-supervised with Luca Peruzzotti-Jametti)
Despite the absence of clinically relevant immune-related attacks, a diffuse activation of the immune system is thought to be one of the major drivers of disease progression in MS. However, differently from relapsing remitting MS, in progressive MS the immune cells that mediate the damage are called mononuclear phagocytes.
Mononuclear phagocytes are not harmful per se, but they become so because of a chronic change in the ways they consume and produce energy. Energy production in a cell (or metabolism) is important for its function. We found that mononuclear phagocytes undergo a “metabolic switch” that makes them chronically active and accumulate one specific metabolite called succinate.
The goal of this approach is to understand how different types of mononuclear phagocytes accumulate succinate during neuroinflammation and to interfere with their metabolism so that they stop damaging the brain. Moreover, thanks to a wide set of biological samples obtained from MS patients, we aim at finding out if succinate (or other metabolites) can be used as a marker to predict disability in MS patients.
- Single-Cell RNAseq Analysis of Reactive Astrocyte Heterogeneity in Spinal Cord Injury (SCI)
(co-supervised with John Marioni and Jayden Smith)
Secondary injury mechanisms in traumatic spinal cord injury are exacerbated by morphological, molecular, and functional changes in astroglial cells (astrocyte reactivity/astrogliosis), which are still not fully characterized. Consequently, therapeutic approaches aiming at the modulation of astroglial reactivity remain controversial.
The goal of this project is to investigate the molecular mechanisms of astroglial cell reactivity in SCI at unprecedented depth by employing the innovative technology of ex vivo single-cell RNA sequencing to obtain high-throughput gene expression profiling.
The candidate working at this project will aim at:
- (i) Profiling the transcriptome of astrocytes isolated ex vivo from moderate and severe mouse models mouse models of moderate and severe contusion SCI at multiple stages (acute, subacute and chronic); and(ii) Analysing and identifying pathways and genes that are critical to the beneficial and detrimental aspects of astroglial cell activation, with a focus on the comparison between the different severities and time points.
- These results are expected to ultimately lead to the identification of novel therapeutic targets for future molecular approaches with significant translational value in complex SCIs and the potential to compare and contrast with other reactive astrocyte profiles in the future.
Professor Chris Rodgers (email@example.com) – WBIC
- Parallel Transmit Pulse Sequence Design for Ultra-High Field (7T) MRI
Cambridge’s Wolfson Brain Imaging Centre has recently installed a new Siemens 7T Terra MRI scanner. This system has the strongest magnetic and the most advanced electronics and control software of any MRI scanner in the UK. The student in this project will work in the new 7T MRI physics group under supervision of Chris Rodgers. He/she will develop new theory and write new software to utilise the 7T Terra system’s 8 independent radiofrequency transmit channels in order to improve the quality of quantitative imaging and spectroscopy in the human brain, and to minimise scan duration and subject heating. These new methods will be applied in collaborative studies with colleagues from the departments of clinical neurology and psychology. Experience in physics or engineering, and an aptitude for mathematics and computer programming would be advantages.
Professor James Rowe (James.Rowe@mrc-cbu.cam.ac.uk) – Neurology/CBSU
- Ultra-High field (7T) MR Spectroscopy of GABA: A Critical New Approach to Dementia
Advances in spectroscopy at high-field MRI (3T), and ultrahigh field MRI (7T, in Cambridge from mid 2016) now enable accurate estimation of cortical GABA, the principal inhibitory neurotransmitter in the cortex. This has a strong influence on individual differences in behaviour, perception and learning. In this new project, you will use the new 7T MRI to determine the contribution of GABA to changes in cognition in dementia (especially Frontotemporal dementia and progressive supranuclear palsy). GABA modulation provides an attractive new target for cognitive enhancement, but you will also determine whether an individuals’ response to treatment depends on their current GABA state. The project emphasises the integration between multiple brain systems for learning, cognition and perception, and how they are affected by neurodegenerative disorders. Experience in neuroimaging, principles and practice, would be an advantage.
- Predicting the Onset and Outcome of Frontotemporal Lobar Degeneration
Frontotemporal lobar degeneration causes several devastating neurodegenerative dementias, such as frontotemporal dementia (FTD) and progressive Supranuclear palsy (PSP). With the scale and success of our long term cohort studies (PiPPIN, GenFI, PROSPECT etc.) and national dementia initiatives which we are involved in (including Dementias Platform UK), comes the opportunity to identify the presence and onset of disease in people before symptoms (eg. in people known to carry a genetic mutation) and to predict the future course of a patient’s illness.
Such predictions are an important step in stratifying and designing treatment studies, and also give important new insights into the mechanisms of human neurodegeneration. Accurate prediction may be based on our advanced brain imaging (especially MRI), or blood measures (biomarkers), genetics or cognition etc. In this unique project, you will be responsible for analysis of our cohort data so as to predict and model the course of disease.
- Synaptic Loss in Dementia: New Approaches to Early Detection and Therapy
In many neurodegenerative disorders, it is the synapse that deteriorates (in number, structure and plasticity) long before cell death and atrophy. Given the critical role of synaptic function in cognition, the ability to measure synaptic function and number in humans would be a great step forward in understanding the earliest stages of human dementia, and in accelerating new treatments. With new specialist PET ligands for synaptic density, and our world class PET imaging facilities, this is now possible. This new project with Professors Rowe, Aigbirhio and O’Brien, builds on our long standing dementia collaboration “NIMROD” that examines the driving pathologies in multiple forms of dementia, and their impact on cognition, through multimodal brain imaging. It will develop your expertise in PET (focussing on synaptic markers), MRI, and cognition in the vibrant and international Biomedical Research Centre dementia research community.
Professor Stephen Sawcer (firstname.lastname@example.org) – Neurology (PhD Only)
- The Genetic Analysis of Multiple Sclerosis
Through genome-wide association studies and related follow up efforts we have identified over 100 genetic variants that influence the risk of developing multiple sclerosis. These variants map almost exclusively to regulatory regions of the genome that are active in immune cells suggesting that these variants primarily exert their effects by altering the expression of otherwise normal genes in critically important immune cell sub-types. In order to try and understand more precisely how these associated variants influence the development of multiple sclerosis we are undertaking a range of projects.
1) In work already completed we have established that at least two of the associated variants influence the expression of key immune signalling genes in B cell sub-types. These data confirm the importance of B cells in pathogenesis which is in keeping with the latest clinical trial data showing the positive effects of anti-B cell therapies. This project will focus on fine mapping the causal variants underlying observed associations by exploring the expression of key immune genes in B cell subtypes. The work will involve mapping of transcription and chromatin architecture, as well as protein expression and cell function.
2) The highly significant overlap in the genetic architecture of immune mediated inflammatory diseases (IMID) suggests that there are key pathways in the immune system that influence the propensity to autoimmunity. This project will use data from UK Biobank (500,000 genotyped individuals) to dissect out the genetic architecture of these common pathways. The project will then use genomewide methylation mapping to fine map associated variants epigenetically and determine the functional effects of these variants.
3) As part of the Cambridge Single Cell Analysis Core Facility we are undertaking single cell expression profiling in cells from the cerebrospinal fluid and blood of patients and controls. This project will allow a transcriptional based taxonomy of immune cells and identify master transcriptional regulators of relevance in multiple sclerosis. The project will also explore the epigenetic signature and functional effects of identified regulators.
The successful student will work closely with colleagues at the McGill University Epigenomics Mapping which is a leading institution in the International Human Epigenome Consortium (IHEC), the project may include the opportunity for willing students to spend a period of their research in Montreal.
Dr Peter Smielewski (email@example.com) – Neurosurgery
- Optimisation of Real Time Analysis of Multimodal Monitoring Data and its Application to Computer Guided Management of critically Ill Patients
In an established environment of neuro-intensive care large quantities of data can be captured from bed-side monitors. This data contains a wealth of information about the pathophysiology of the critically ill patient however the extraction of this information often requires sophisticated signal analysis. Such analysis is usually performed using universal data analysis packages like Matlab but requires engineering/mathematics expertise and is only available in off-line mode and as such in not applicable in a clinical setting. Our own software ICM+ (http://www.neurosurg.cam.ac.uk/icmplus), which is by now used in many clinical centres worldwide, attempts to bridge the gap between laboratory and clinical application. It collects data from bedside monitors, calculates in real time ‘secondary’ parameters defined using highly configurable signal processing formulae and produces continuously updated charts. This way complex information coming off the bedside monitors can be summarized in a concise fashion and presented to medical staff in a simple way that alerts them to the development of various pathological processes. The projects offered will include the following stages:
- Development of new methodologies of analysis of physiological signals acquired in the Neuro Intensive Care, including time and frequency domain, stationary and non-stationary methods, linear and non-linear approaches.
- Validation of the new methodologies against retrospective and prospective data from the Neuro Intensive Care unit
- Implementation of the novel algorithms into ICM+ plugins, packaged as Windows dll libraries, so that they can be used in real time by the bed side These projects would suit graduates in Biomedical Engineering, but also potentially Physics, Mathematics, and Computer Science.
Dr Emmanuel Stamatakis (firstname.lastname@example.org) – Anaesthesia
- The default mode network in consciousness (PhD/MPhil)
Brain injury management has improved considerably in recent years with resulting significant improvements in outcome. Nevertheless, a small but significant number of survivors do not fully emerge after acute coma and remain in prolonged disorders of consciousness (DoC), including vegetative and minimally conscious states. Long range brain networks, such as the default mode network (DMN), have been shown to be disrupted in DoC, and are partially or fully restored when patients recover cognitive capacity. The functional role of the DMN remains unclear. Although it was initially considered to be a task negative network, recent studies from our group and others have revealed DMN activity/connectivity during a wide range of self-referential and memory-based tasks, as well as altered DMN integrity in a variety of neuropsychiatric disorders. Such data provide support for inferences on the role of the DMN in cognitive capacity and consciousness. An emerging theory is that the DMN acts as global workspace integrating information from a variety of sources through associations, to make sense of the world at present. The major hubs of the DMN are multisynaptic and are connected to both cortical and subcortical regions rendering this network a suitable candidate for integrating information. Within this emerging theoretical framework this project will utilise fMRI/EEG to focus on the role of the DMN at rest but also importantly during tasks, in a cohort of DoC patients and healthy volunteers. Experience in neuroimaging and/or electrophysiology is required for this project. Skills in scientific computing and programming (e.g, Linux, Matlab, Python) are desirable.
- Functional MRI imaging in Traumatic Brain Injury (PhD/MPhil)
CENTER-TBI is a large European project that aims to improve the care for patients with Traumatic Brain Injury (TBI). The work undertaken in Cambridge will examine the role of MRI in routine TBI imaging and this project will focus on the role of resting state functional MRI in TBI imaging. There is now abundant evidence from functional MRI suggesting that the resting brain is organised in coherent long range networks. The functionality of these networks is easily inferred since they typically track the functional anatomy of networks identified during activation studies. For this reason, the translational potential of resting networks, particularly in patients unable to participate in stimulus driven experiments (e.g. TBI), seems immense but is mostly unrealised. This project will evaluate the usefulness of resting state functional MRI imaging in TBI for understanding and tracking disease processes and prognosticating cognitive recovery. Additionally we will aim to relate functional connectivity patterns to cognitive measures, vulnerability for depression and to functional outcome in general. Experience in neuroimaging, in particular MRI analysis, is required for this project. Some programming experience (e.g, Linux, Matlab, Python) is desirable.
- Biomarkers for risk and clinical outcome prediction of postoperative cognitive dysfunction (PhD/MPhil)
Postoperative cognitive impairment is increasingly prevalent in our aging society. This condition often has an acute phase of Postoperative Delirium (POD) which may then be followed by a more chronic phase of Postoperative Cognitive Dysfunction (POCD), which tends to persist over time. BIOCOG, a European FP7 funded project, aims to establish biomarkers for risk and clinical outcome prediction of POD/POCD. The study population are patients aged 65 to 80 undergoing major elective surgery. The work undertaken in Cambridge will focus on MRI imaging and will investigate whether brain network properties obtained from MRI diffusion tensor imaging (DTI) measures, relate to those obtained from resting state functional MRI data. Structural and functional network properties will be related to neuropsychological and clinical measures. Experience in neuroimaging, in particular MRI analysis, is required for this project. Skills in scientific computing and programming (e.g, Linux, Matlab, Python) are desirable.
Dr Patrick Yu-Wai-Man (email@example.com) – Neuro-Ophthalmology and Genetics (PhD Only)
I am an academic neuro-ophthalmologist with a major research interest in mitochondrial genetics and inherited eye diseases. My research group is focused on new gene discovery and we are using a multipronged approach to dissect the disease pathways contributing to progressive neuronal loss and blindness, including zebrafish models and patient-derived induced pluripotent stem cells.
I coordinate a specialist clinical service for patients with mitochondrial eye diseases in Cambridge, Newcastle and London. Over the past 15 years, we have established a national cohort of patients with inherited optic neuropathies, and we are using this unique resource for deep phenotyping, biomarker profiling and to push forward with an active translational research programme, including gene therapy.
I have long-standing collaborations with other principal investigators in the Cambridge Centre for Brain Repair, the Cambridge MRC Mitochondrial Biology Unit and the UCL Institute of Ophthalmology in London. This extensive research network will provide the student with access to a wide source of expertise, tailored supervision and the opportunity to develop a broad skill set as the project evolves.
- Yu-Wai-Man P, Newman NJ. Inherited eye-related disorders due to mitochondrial dysfunction. Human Molecular Genetics. 2017; Epub ahead of print.
- Yu-Wai-Man P, Votruba M, Burté F, La Morgia C, Barboni P, Carelli V. A neurodegenerative perspective on mitochondrial optic neuropathies. Acta Neuropathologica. 2016;132:789-806.
- Burté F, Carelli V, Chinnery PF, Yu-Wai-Man P. Disturbed mitochondrial dynamics and neurodegenerative disorders. Nature Reviews Neurology. 2015;11:11-