Applications for entry to our Postgraduate (Research) Training Programme for admission in academic year October 2017 – September 2018
Deadlines for applications for admission in the academic year October 2017 – September 2018 are as follows:
*For those who wish to apply for a PhD or MPhil you can apply up until 31 May 2017, these are only for those that are able to fund positions as the funding round has closed. Please go to links below to apply.
PhD in Clinical Neurosciences http://www.graduate.study.cam.ac.uk/courses/directory/cvcnpdpcn
MPhil in Clinical Neurosciences http://www.graduate.study.cam.ac.uk/courses/directory/cvcnmpmds
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 made will be early June followed by interviews, dates to be confirmed**
*For those who wish to be considered for funding, this has now passed, deadlines as below:
Gates USA : 12 October 2016
UK, EU and overseas applicants: 7 December 2016
* IMPORTANT – this included applications from applicants who wish to be considered for Cambridge Trust funding (both inside and outside the EU).
*** If you have been short listed for interview, you will be contacted by email***
Research projects for 2017/18
Research projects available (start dates: October 2017, January 2018, April 2018). 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 2017/18. Follow the links to find out more information about the supervisor and group. For more information about a specific project please contact the individual supervisor using the e-mail address provided. 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.
Professor Roger Barker (email@example.com) – Neurology/ J v G Centre for Brain Repair
Factor that influence financial decision making in Huntington’s disease
(Co-Supervised by Dr Sarah Mason)
Advances in technology have changed the way in which we spend and manage our money. For most this has been a liberating development but for the 750000 people living with dementia in the UK today this poses serious challenges to their ability to live independently and puts them at increased risk of financial abuse. A recent report from the Alzheimer’s society identified that scams such as cold calling, scam mail or mis-selling have cost dementia patients and their families in the region of £100 million (Alzheimer’s Society, 2011). Furthermore, changes to social care services in the UK mean that people with dementia now have the freedom to control their own care package through the introduction of personal budgets and Direct Payments (Duffy, 2010) but conversely this may have further contributed to their financial vulnerability. The Mental Capacity Act (2005) offers protection to patients who lack the capacity to make financial decision for themselves by extending their right to appoint a proxy decision maker but it offers few safeguards for those in the early stages of dementia or those who do not have a friend or family member to take on this role.
Using Huntington’s disease as a model of dementia, we will seek to identify the social, emotional and cognitive changes that directly impact upon financial decision making. Using multiple different experimental techniques in premanifest HD gene carriers and patients with early disease this project will seek to identify predictors of future financial vulnerability.
Sleep, circadian, and cognitive disturbances in Huntington’s disease
This is a clinical research project involving patients with pre-manifest and manifest Huntington’s disease (HD). We aim to perform a detailed prospective sleep and circadian study to clarify the extent to which sleep and circadian disturbances are associated with, and predict, disease onset and progression in HD. We aim to perform detailed analyses of sleep and wake dependent brain electric activity (EEG) and the effect of sleep on cognition in association with markers of the intrinsic circadian rhythmicity as well as assess the efficacy of different therapeutic interventions OR DRUGS on this.
Dr Dennis Chan (firstname.lastname@example.org) – Neurology
Virtual reality-based testing of entorhinal cortex and hippocampal function in people at risk of Alzheimer’s disease
The aim of this project is to detect changes in the function of the entorhinal cortex (EC) and hippocampus in people at risk of developing dementia due to Alzheimer’s disease (AD). The EC, and subsequently the hippocampus, are the first cortical regions to exhibit neurodegeneration in AD and thus detection of early alteration in their function would both aid diagnosis of AD in its very earliest stages and identify a “sweet spot” early in the disease when disease-modifying therapies may be of maximal benefit.
Knowledge of EC and hippocampal function drawn from cell and systems neuroscience will be applied to this study of early AD, specifically the extensive evidence that these regions play a critical role in spatial processing. EC (grid cells) and hippocampal (place cells) neurons have spatially-related firing activity which correlates behaviourally with spatial navigation and memory. We have already shown that spatial memory testing is highly sensitive and specific for pre-dementia AD, and this project will use immersive virtual reality (iVR) technology to assess navigation and memory in virtual environments. Subfield-resolution analyses of EC-hippocampal structure and connectivity obtained from 3T and 7T MRI scanning will provide imaging correlates of these behavioural data.
This novel approach will build on past work by i) testing EC as well as hippocampal function in at-risk cohorts, thus extending the detection of AD into even earlier stages of disease, ii) applying behavioural tests analogous to those used to test EC-hippocampal function in animal models of AD, thus addressing a major unmet need in translational AD research.
Modifiable contributors to cognitive reserve and their neural correlates (co-supervisor: Professor Rik Henson, MRC Cognition and Brain Sciences Unit)
Cognitive reserve (CR) is considered to mediate the relationship between brain health and cognition, such that individuals with high CR maintain cognitive function in the face of declining brain health due to age and age-related diseases such as Alzheimer’s disease. Factors contributing to CR include intelligence, education, physical health and “non-specific mental activity” in middle age (MN), which encompasses cognitive (reading, learning a new language) and physical (playing sport) activity.
The central hypothesis of this study is that MN contributes to CR, independent of intelligence and education. Proof of hypothesis would have major implications given the potential modifiability of MN in adult life and the attendant implications for reducing the future risk of developing dementia. Our analyses of the CamCAN (Cambridge Centre for Ageing and Neuroscience) cohort have provided initial support for this hypothesis. The aims of this PhD project are:
- i) to replicate the CamCAN findings in an independent cohort with superior MN associated with high levels of adulthood cognitive activity (Fellows of Cambridge Colleges)
- ii) to determine whether the cognitive component of MN is dissociated from the physical component by additionally studying an age-matched cohort of individuals with superior MN associated with high levels of adulthood physical activity (older age athletes)
3. iii) to establish the neural correlates of MN in terms of MRI-derived structural and functional connectivity measures (eg functional segregation of brain networks, topological measures of network architecture)
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.
Nuclear mitochondrial communications: genetic and epigenetic mechanisms
(Collaboration with Prof Anne Fergusson-Smith, Dept of Genetics)
The relationship between mitochondria and the host cell is the most enduring symbiotic relationship in biology, but very little is known about the cross-talk between the two partners. There is emerging evidence suggesting that epigenetic control of both mitochondrial DNA (mtDNA) and nuclear DNA may play a role in this interaction. Metabolites and the energetic state of the mitochondrion can influence key enzymes responsible for nuclear DNA methylation, and thus gene expression. In turn, this then influences energy production by the mitochondrion. Conversely, mtDNA is also methylated by enzymes synthesised from nuclear genes, with the potential to regulate mtDNA gene expression. The aim of this project is to define the key controlling mechanisms underpinning the inter-genomic communication. This will have important implications for human development, and common diseases including cancer, diabetes, neurodegeneration and dementia.
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 Robin Franklin (firstname.lastname@example.org) – Stem Cell Neurobiology/WT-MRC Cambridge Stem Cell Institute
The regenerative biology of adult CNS stem (progenitor) 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. An example of the sorts of projects available concerns adult progenitor heterogeneity and its implications for regeneration. We have recently shown that the developmental origin of CNS progenitors determines how they respond to injury and contribute to remyelination. We have also shown that the detrimental effects of ageing on remyelination effect different progenitor populations in different ways. However, we still have much to learn about the mechanisms that underlie these differences. Using state-of-the-art genomic approaches there is an exciting project to be undertaken identifying differences in genes expression and their epigenetic regulation, and what the functional consequences of these differences might be.
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
Professor Hugh Markus (email@example.com) – Neurology
(For STUDENTSHIP options in this group please go to http://www.jobs.cam.ac.uk/job/12487/, applications can go to Catherine on firstname.lastname@example.org. Deadline to apply 22 January 2017)
Generation of an induced pluripotent stem cell (iPSC) based model of large-vessel ischemic stroke associated with HDAC9 genetic variant
Supervisors – 1st Alessandra Granata, 2nd Hugh Markus & Sanjay Sinha
Stroke is the second leading cause of death worldwide, causing more than one in ten of all deaths and more than six million deaths annually. We recently identified, using a Genome-wide association study (GWAS) approach, the first genetic variant causing common ischaemic stroke which is in the Histone Deacetylase 9 Gene (HDAC9). 1 This specifically predisposes to stroke by causing atherosclerotic narrowing of the arteries to the brain. The protein produced by which could potentially affect chromatin packing and epigenetic influences. It offers an exciting therapeutic possibility, particularly as non-specific HDAC9 inhibitors used to treat epilepsy have been shown to be associated with reduced stroke risk in the population. However, the exact mechanism by which the genetic variant increases the risk of stroke is unknown and this is important if we are to develop more specific therapies. Furthermore to screen for more specific therapies we need models in which to perform drug screening.
This studentship will involve establishing a novel HDSC9 iPSC model to investigate the pathophysiological mechanisms of stroke, which could lead to the development of new effective therapies.
The project involves:
- Generation of human iPSC from patients and targeting of HDAC9 variant using CRISPR/Cas9-mediated gene editing technology to restore the wt allele.
- Differentiation of HDAC9 iPSC and CRIPSR/Cas9 edited lines into the cerebrovascular cell types: vascular smooth muscle cells of neuroectoderm/neural crest embryonic origin (SMC), endothelial cells (EC) and astrocytes2,3. These cells will be characterised for their morphology and functions, using cell-based assays including proliferation/migration, contractility, extracellular matrix degradation, cell viability for SMC and permeability for EC.
- Establishing co-culture of SMC, EC and astrocytes using a trans-well system to model the blood brain barrier (BBB) function and inflammatory responses.
- Identifying novel pathways and regulator genes involved in the pathogenesis of stroke by RNA sequencing (RNA-seq) of HDAC9 variant and CRIPSR-corrected iPSC-derived SMC, ECs and astrocytes.
a.) 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).
b.) 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).
c.) 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; 1st Dan Tozer & 2nd Hugh Markus
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, on structural networks, is a strong predictor of cognitive decline (Lawrence et al. Neurology, 2014;83:304-311).
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.
MRI derived Oxygen Extraction Fraction as a Marker of Dementia Development in Small Vessel Disease
Supervisors; 1st Dan Tozer & 2nd Hugh Markus
Small vessel disease (SVD) of the brain causes 20% of strokes and is the main cause of vascular dementia, it is poorly understood why some SVD patients develop cognitive impairment, and later vascular dementia, but others do not. An understanding of the mechanisms underlying dementia in SVD may lead to prediction of onset and progression of clinical impairment.
Magnetic Resonance Imaging can be used to study many aspects of the brain’s haemodynamic system, including the oxygen extraction fraction (the amount of oxygen taken out the blood as it flows through the brain), the rate of blood flow through the brain (cerebral blood flow, or perfusion) and functional MRI (fMRI) which measures the change in blood flow to an area of the brain as it is activated by a task. These parameters have been shown to be altered in dementia [Tak et al. Neuroimage 2011:55;176-184, Schuff et al. Alzheimer’s Dement. 2009;5:454-462], including work that has shown that subjects with SVD and dementia had a reduced cerebral blood flow and increased oxygen extraction rate compared to similar subjects without dementia.
The aim of this project is to develop a model of the haemodynamic system in subjects with SVD as measured by a number of MRI parameters which probe aspects of blood behaviour in the brain, how this differs from control subjects and how they relate to the development of cognitive impairment and vascular dementia in these subjects. The student will implement and optimise two sequences from which the oxygen extraction fraction can be estimated [He and Yablonskiy Magn Reson Med 2007;57:115–126, An and Lin Magn Reson Med 2003;50:708–716]. The sequences will be applied to controls and SVD patients with varying levels of cognitive impairment (as measured using standard cognitive tests) to assess variation in the oxygen extraction fraction. We will also include brain perfusion and fMRI sequences in the protocol to answer a number of questions:
- How common is increased oxygen extraction fraction in SVD compared to control subjects?
- What is the spatial pattern of the increased oxygen extraction fraction in SVD patients?
- Is increased oxygen extraction fraction present in all stages cognitive impairment in subjects with SVD?
- Does the oxygen extraction fraction change as a function of cerebral blood flow?
- Is the signal change seen in fMRI experiments modulated by the oxygen extraction fraction? In particular are volumes of activation dependent on the haemodynamic state of the tissue.
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.
Cerebral Small Vessel Disease and Vascular Cognitive Impairment: Improving Understanding of Mechanisms with a view to Improving Treatment
Supervisor Professor Hugh Markus, Professor of Stroke Medicine
Cerebral Small Vessel disease represents an enormous health problem. It causes about a quarter of all strokes and is the main pathology underlying vascular cognitive impairment and vascular dementia, which itself is the second most common cause of dementia after Alzheimer’s disease. In addition we now understand that it interacts with Alzheimer’s disease to increase the chance someone with AD pathology will develop clinical dementia.
We have pioneered the use of advanced MRI techniques to better understand disease mechanisms and using Diffusion Tensor Imaging (DTI) have shown the role of white matter disruption leading to this connection and disruption of complex brain networks. Recently we have applied MRI techniques for visualising both structural and functional networks and shown disruption of these is the key process in causing cognitive impairment
The student will join this exciting programme and carry out a series of studies further investigating the mechanisms of cognitive decline in this disease, how vascular and neurodegenerative processes (e.g. AD) interact, and how better understanding of these processes can allow us to develop more rational treatment approaches. They will apply both advanced MRI techniques and cognitive testing. This project would be ideal for a psychologist or neuroscientist who is keen to become involved in MR image analysis.
Professor Keith Martin (email@example.com) – J v G Centre for Brain Repair / Ophthalmology
Regenerating the optic nerve (co-supervised with Prof James Fawcett)
If damage to the optic nerve or retinal ganglion cells is to be repaired, it is necessary for axons to regenerate from the retina to the brain; at present this is not possible. The project will develop new methods to stimulate axon regeneration from the retina to the brain. The first method will be based on expressing integrins and integrin activators in ganglion cells, which has been dramatically successful in the spinal cord. The second method will be to activate signalling via phosphatidylinositols to stimulate axonal transport and motility. The project will also examine guidance of regenerating axons. Co-supervised by Professors James Fawcett and Keith Martin.
Lorber B, Chew DJ, Hauck SM, Chong RS, Fawcett JW, Martin KR (2015) Retinal glia promote dorsal root ganglion axon regeneration. PLoS ONE 10:e0115996.
Tan CL, Andrews MR, Kwok JC, Heintz TG, Gumy LF, Fassler R, Fawcett JW (2012) Kindlin-1 enhances axon growth on inhibitory chondroitin sulfate proteoglycans and promotes sensory axon regeneration. J Neurosci 32:7325-7335.
Stem cells for the treatment of eye disease
We have developed techniques to test the effectiveness of stem cell transplantation in models of glaucoma, the leading cause of irreversible blindness worldwide. We have shown strong neuroprotective effects of transplantation of mesenchymal stem cells (MSC) and oligodendrocyte precursor cells in models of glaucoma. Most recently, we have demonstrated that Platelet-derived Growth Factor (PDGF), produced in high levels by MSC, provides extremely robust neuroprotection when delivered intravitreally and appears to mediate most of the neuroprotective effect of MSC transplantation (Johnson TV et al, Brain 2014). This project will explore further the potential of PDGF and MSC therapy for the treatment of glaucoma. We have recently acquired the equipment required to assess behavioural visual function in our animal models and an aim of the project will be to quantify the level of functional protection afforded by different potential therapies.
Tassoni A, Gutteridge A, Barber AC, Osborne A, Martin KR. Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation. Stem Cells. 2015 Jul 14. doi: 10.1002/stem.2095. [Epub ahead of print]
Johnson TV, DeKorver NW, Levasseur V, Osborne A, Tassoni A, Lorber B, Heller JP, Villasmil R, Bull ND, Martin KR*, Tomarev SI*. Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor (PDGF) through analysis of the mesenchymal stem cell secretome. Brain. 2014 Feb;137(Pt 2):503-19.. PMID: 24176979 *Joint senior and corresponding authors
Johnson TV, Martin KR. Cell transplantation approaches to retinal ganglion cell neuroprotection in glaucoma. Curr Opin Pharmacol. 2013 Feb;13(1):78-82. doi: 10.1016/j.coph.2012.08.003. Epub 2012 Aug 29. PMID: 22939899
Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI, Martin KR.
Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Invest Ophthalmol Vis Sci. 2010 Apr;51(4):2051-9
Is myelination important for neuronal circuit development?
A critical period in brain development is the point at which a sensory experience regulates the proper development of a particular brain circuit. If the circuit is tampered with during this period, that circuit will be permanently compromised1. The developing visual circuit pathway is one of the most extensively studied circuits. The role of myelination during this development, which potentially regulates the timing of retinal ganglion cell inputs, is unknown.
Children who suffer from cataracts during the critical period of visual circuit development can develop amblyopia and have altered myelination in their visual pathway2. The critical period for establishing the retinogeniculate circuitry3 aligns with the timing for myelination of the optic nerve4. This project will investigate this fundamental question, whether myelination may regulate refinement of neuronal circuits.
1. Hensch, T. K. Critical period plasticity in local cortical circuits. Nat. Rev. Neurosci. 6, 877–888 (2005).
2. Jr, E. G., T, F. & Rz, G. Myelinated nerve fibers, axial myopia, and refractory amblyopia: an organic disease. J. Pediatr. Ophthalmol. Strabismus 24, 111–119 (1986).
3. Hooks, B. M. & Chen, C. Critical Periods in the Visual System: Changing Views for a Model of Experience-Dependent Plasticity. Neuron 56, 312–326 (2007).
4. Foster, R. E., Connors, B. W. & Waxman, S. G. Rat optic nerve: electrophysiological, pharmacological and anatomical studies during development. Brain Res 255, 371–386 (1982).
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
Induced neural stem cells and RNA nanotechnology: a combinatorial approach to brain and spinal cord injuries (with Jayden Smith, PhD)
Our lab is investigating combinatorial approaches employing complementary state-of-the-art technologies to overcome these hurdles, with an eye towards developing novel clinical therapies for CNS disorders. Specifically, we will employ RNA nanotherapeutics, designed to ameliorate CNS insults via gene regulation or cell reprogramming, in combination with the transplantation of next-generation stem cell technology intended to promote regeneration. This project will see the student designing and synthesising novel multifunctional packaging RNA (pRNA) nanostructures intended to deliver gene expression-modulating RNA interference payloads to appropriate neural cells. Various RNA nanotherapeutics, or combinations thereof, will be assayed in appropriate in vitro cell cultures via method such as quantitative PCR, Western blot, and immunocytochemistry. Having identified effective therapeutic approaches in vitro, the student will progress to in vivo studies, testing the nanotherapeutics in the context of appropriate animal models of injury or disease. Nanotherapeutic approaches will be tested alone, in combination, and in conjunction with the transplantation of induced neural stem cells (iNSCs). iNSCs are a promising alternative to both natural NSCs and induced pluripotent stem cells (iPSCs), avoiding the issues regarding the difficulty of acquisition of the former and the potential safety issues of the latter. Our ultimate goal is to effect anatomical and functional recovery in animal models using this combinatorial approach, demonstrating the clinical potential of such an approach.
Exosome-mediated Stem Cell Signalling to the Immune System (with Nunzio Iraci, PhD)
EVs are small membranous structures limited by a lipid bilayer that are observed in virtually every form of life. In recent years, several works have shown that a variety of cell types are capable of releasing EVs in the extracellular space both in vitro and in vivo. Notably, EVs contain soluble components (e.g. proteins, metabolites and nucleic acids) that have been implicated in a broad range of physiopathological processes, such as intercellular signalling, immunity, and cancer. We have recently shown that neural stem cell-derived EVs are able to (i) dynamically modulate their content – including messenger and microRNAs – in response to environmental stimuli; and (ii) transfer information to the microenvironment. We have also collected preliminary evidences that EV treatment: (i) inhibits the proliferation of T lymphocytes; (ii) reduces the activation of LPS-stimulated bone marrow-derived macrophages (BMDM). In addition, we have collected preliminary evidences suggesting that EVs bear functional enzymatic activities capable of modifying the metabolic landscape of the inflammatory microenvironment. We hypothesise that NSC-derived EVs would impact different arms of the immune response by using specific and possibly complementary mechanisms.
Here we propose to investigate putative immune modulatory mechanisms of NSC-EVs on immune cells. Specifically, we will investigate the relevance of two different classes of candidate EV-associated molecules in NSC-mediated immune modulation. By investigating how NSCs signal to the host immune system, we will be able to understand how to harness the immune system for improved outcomes in regenerative medicine
WNT3A in macrophage-mediated angiogenesis (with Almudena Fuster, PhD)
Ischemic stroke is currently the leading cause of adult chronic disability, the second most common cause of cognitive impairment and the third most frequent cause of mortality in industrialised countries. Wnts and Wnt ligands (Wingless-related MMTV integrated site) are a family of secreted glycoproteins orchestrating a wide range of processes in the developing and adult brain, including neural induction and patterning, cell proliferation, synaptogenesis, adult neurogenesis and regeneration. Wnt signaling also regulates angiogenesis, whereas its clear role is yet to understand. Among a number of cellular and molecular mechanisms, thrombosis and hypoxia trigger an intravascular inflammatory cascade, which is further augmented by the innate immune response occurring in the central nervous system (CNS) parenchyma (neuroinflammation). In this context, macrophages play an important role in angiogenesis during hypoxic conditions, where they up regulate more than 30 pro-angiogenic genes.
The expression of Wnt ligands and Wnt signalling molecules has only recently been identified in immune and immune-like cells, including macrophages, which play a significant role in both physiological and pathological angiogenesis where they have been suggested to be pro-angiogenic at least in a tumor microenvironment.
The objectives of this project will be to study:
1) The role of Wnt3a in promoting a pro-angiogenic phenotype in macrophages as well as its direct role on ECs trying to clarify the importance of macrophages in the process;
2) The molecular pathways responsible for this effect and the ones responsible for the angiogenic response in Endothelial cells (ECs).
Knowing the specific functions of the different Wnt ligands in macrophage-mediated angiogenesis, shall help to understand, not only the role of this ligand in the process and the contribution of the immune system to this, but also to inspire the development of new therapies for stroke based on the modulation of this pathway.
Professor James Rowe (James.Rowe@mrc-cbu.cam.ac.uk) – Neurology/CBSU
Decision making in dementia
Decision models can explain many cognitive and behavioural phenomena in health (eg. accumulator models, drift diffusion models). Recently, this approach has been extended to direct the analysis of fMRI and M/EEG data in our group, for example by estimating latent cognitive and neural processes from behaviour as predictors of neuroimaging activation. This alignment of cognitive process and neural mechanism for decision making is directly relevant to many areas of cognitive neuroscience, including dementia. You will use these powerful modelling tools to investigate perceptual and motor decisions in neurodegenerative dementias, which can also include the combination of decision models with drug therapies, and functional brain imaging. A background in computational neuroscience (eg. in your BSc or MSc) would be an advantage.
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.
Professor Stephen Sawcer (SJS1016@cam.ac.uk) – Neurology
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 (firstname.lastname@example.org) – 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:
1. 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.
2. Validation of the new methodologies against retrospective and prospective data from the Neuro Intensive Care unit
3. 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 A Stamatakis (email@example.com) – 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 group of survivors do not fully emerge after acute coma and remain in a prolonged disorder of consciousness (DoC), including the vegetative (VS) and minimally conscious (MCS) states. Long range resting brain networks, such as the default mode network (DMN), have been shown to be disrupted in VS, 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 the DMN a suitable candidate for integrating information. Within this emerging theoretical framework this project will utilise fMRI to focus on the role of the DMN at rest but also importantly during tasks in a cohort of DoC patients and healthy volunteers.
Functional MRI imaging in Traumatic Brain Injury (PhD/MPhil)
CENTER-TBI represents a focused European effort to advance the care of patients with traumatic brain injury (TBI), within the broader international framework of InTBIR (International Initiative for Traumatic Brain Injury Research). 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 in healthy controls is organised in coherent long range networks. The functionality of these resting networks is easily inferred since they typically track the functional anatomy of brain areas shown to act in synchrony during activation paradigms. 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 MRI imaging in the subacute TBI phase, for understanding and tracking disease processes, prognosticating cognitive recovery and mapping covert cognition in disorders of consciousness and at the chronic phase, aiming to relate functional connectivity patterns to cognitive measures, vulnerability for depression and to functional outcome in general.
Spontaneous brain activity in acute and chronic pain states (MPhil)
Chronic pain is a challenging health care problem, and when severe, is often accompanied by depressive symptoms and anxiety. Unsurprisingly, disruption of several long range spontaneous brain networks is observed in patients with chronic pain. Of them, the default mode network (DMN) is most consistently affected, but is either under or over active in studies with patients with chronic pain compared to healthy controls. These contradictory studies are robust but interpretation of the findings is challenging and relies on control of confounds related to medication use and affective disorders that themselves alter the DMN. This project seeks to map DMN function/connectivity during an episode of constant pain that is experimentally induced in healthy subjects. The project involves analysis of functional MRI data. There will be scope of acquiring and analysing new datasets to compare DMN in patients with chronic pain, comparing those with and without symptoms related to depression. Project jointly supervised with Dr Michael C Lee (firstname.lastname@example.org).
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 graph properties obtained from MRI diffusion tensor imaging (DTI) measures, relate to those obtained from functional MRI data. Specifically, we will investigate whether resting state functional connectivity is a complex or otherwise manifestation of structural connectivity by exploring similarities and differences utilising graph theory. Differences between structural and functional graphs will be related to neuropsychological, psychological and clinical measures from the study population. Our hypothesis is that DTI derived graphs represent a ground truth and greater functional variations from them represent healthier brains.