Applications for the Academic year October 2020- September 2021 open 2^nd September,  Funding deadlines are as follows:

Gates US: 9^th October 2019

Postgraduate Funding Competition (all other funders including Gates Cambridge): 3^rd December 2019

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

(Applications for Michaelmas 2020, Lent and Easter 2021 are still being considered, but funding must already be secured, deadlines available here)

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 (fia20@medschl.cam.ac.uk) – Wolfson Brain Imaging

Synthesis and Evaluation of Novel Molecular Imaging Probes for Imaging Aggregated Protein Structures linked with Neurodegenerative Diseases

This project’s objective is to develop novel molecular imaging probes, including 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.

Novel Carbon-11 and Fluorine Radiochemistry for Manufacture of PET Radiopharmaceutical

This project is focused on developing novel radiosynthetic methods for carbon-11 and fluorine-18 to widen the scope of radiolabelling method and produce simpler, more robust methods for the manufacture of PET radiopharmaceuticals. Novel technologies will be applied include flow chemical/microfluidic methods and micro-capillary films.

*NOTE: these projects are particularly suited to graduates in chemistry.

Edward Avezov (ea347@medschl.cam.ac.uk) – UK Dementia Research Institute

(PhD or MPhil, PhD preferable)

 Endoplasmic Reticulum Transport and Morphoregulation in Neuron (Patho) Physiology

The Endoplasmic Reticulum (ER) is a multifunctional organelle, shaped as a contiguous network of membranous pipes extending throughout the cell periphery. Its morphology benefits intercellular communication, allowing controlled distribution of ER luminal solutes (e.g. Ca²⁺ in muscular/neuronal signaling) and membrane bound components to distant sites and adjoining organelles. Mounting data points to a critical role of ER morphology regulation in neuronal functioning. This is prominently exemplified by the direct association of ER morphogens (aka ER shaping proteins) with neuropathologies such as Hereditary Spastic Paraplegia and dementia related diseases. We seek understanding of how ER’s network integrity, morphological regulation and luminal transport support neuronal cell functioning, with a view to identifying new intervention targets for prevention of neurodegenerative avalanche. The projects involves editing of candidate genes in cells with potential to differentiate to neurons/glia, and analysing the consequences of the targeted mutagenesis on structure/function of neuronal ER using live cell microscopy techniques such as super-resolution imaging and single particle tracking (carried out in collaboration with optics physicists and computer scientists).

Endoplasmic Reticulum Associated ROS and Redox Dynamics in Neurons

Reactive Oxygen Species (ROS) are utilized by cells as secondary messengers. Fine time-space regulation of ROS is vital to avoid their toxicity. Elevated ROS (oxidative stress) accompany dementia pathologies. Endoplasmic Reticulum (ER) and its insulated and regulated redox system emerges as key player in physiological and controlled supply of certain ROS and may be also a source of the pathological oxidative stress. The project aims to explore this notion and identify the factors endowing the ER with its ROS production, storage and supply capabilities. Work involves utilizing (and further development) of genetically encoded probes for live cell redox and ROS imaging in genetically and pharmacologically manipulated neurons.

Monitoring Protein Aggregation and Aggregates’ Handling by Neurons

Cells maintain dynamic protein homeostasis, ensuring a manageable load of unfolded proteins and adequate availability of the protein folding machinery. In healthy proteostasis nascent proteins are chaperoned through the functional folding route avoiding misfolding and aggregation. Dementia related pathologies are associated with a disbalanced proteostasis manifested in aggregation of several particularly aggregation-prone proteins (e.g. TAU, a-betta, a-synuclein etc.). In this project we develop live-cell- imaging-compatible aggregation-sensing techniques to study cellular mechanisms and factors behind aggregation-predisposing cellular conditions, and those involved in aggregates’ turn-over.

Professor Manohar Bance (mlb59@cam.ac.uk) Cambridge Ear Institute

Hearing Related Projects:

Developing New Tests for Site of Lesion in Hearing Loss

(PhD- suitable for clinical otology, audiology or auditory science backgrounds)

(co-supervised by 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, particularly in those with known genetic lesions. We will liaise with animal researchers to validate these models, using pharmacologic, noise and other traumas to develop specific lesions, and by using genetic knockout mice with known sites of pathophysiology to corroborate our findings in patients.

Developing Synthetic Models of the Cochlea to Investigate Cochlear Implant Stimulation Spread

(PhD- suitable for engineering, materials, chemical engineering and biomedical backgrounds)

 (co-supervised by Professor George Malliaras, Dr Debi Vickers and 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 biomaterials to 3D print cochlear implant models that are optimized to have similar electrical impedances to living cochlear bones, with embedded sensors to measure current and EMF spread profiles. This platform will be used to develop new methods of electrical stimulation from cochlear implants that allow for more sophisticated focusing of electrical activity to increase the frequency resolution of current cochlear implants. We aim to also seed these structures with auditory spiral ganglion cells (separate PhD) and inflammatory cells to look in-vitro at the complex interaction between electrical stimulation, neural activation and foreign body inflammatory reactions.

Developing 3-D Reconstructed Models of the Human Cochlea, and using them to Develop the Material Properties for Cochlear Implants for a Range of Anatomies

 (PhD- suitable for clinical otology, imaging, or anatomy backgrounds)

(co-supervised by Dr Andrew Gee & Dr Graham Treece)

There is a huge variation in the anatomy and size of the human cochlea. This project develops 3D models of the human cochlea from microCT scans, and using imaging statistical tools to develop models of variation. The different geometries are then 3D printed, and used as templates to develop the material properties for different types of electrode arrays that are optimized to differing geometries.

Developing platform in-vitro constructs of the human inner ear for rapid assay and development of new therapies for hearing loss.

(PhD- suitable for cell biology or materials/biomedical engineering or 3D printing backgrounds)

(Co-supervised by Profesor George Malliaras, Dr. Shery Huang, and Dr Roisin Owens)

We are building “cochlea-on-a-chip” early prototypes, particularly focusing on the stria vascularis, which is damaged with aging. We will embed cation-sensors, voltage sensors and 3D organoid cultures of various cochlear cell types, including stria vascularis cells, auditory spiral ganglion cells, and hair cells. The goal is to develop platforms for rapid screening of drugs and other therapies to restore hearing in damaged inner ears.

Testing and Developing New Interrogation Tools for Cochlear Implant Patients

(PhD, co-supervised by Dr. Bob Carlyon and Dr. Debi Vickers-suitable for audiology, otology, engineering or signal analysis backgrounds)

We run a clinic for patients who are struggling with cochlear implants. We have developed a range of novel tests to interrogate objectively how CIs function, in order to understand better where the problems might be in these patients. This PhD would analyse and develop our tests to date, and correlate test results with functioning of the cochlear implants

Vestibular and Balance Related Projects

(PhD, suitable for otology, audiology, physiotherapy, computational, engineering or biomechanics backgrounds)

We have a particular interest in rehabilitation technologies for vestibular disorders. There are a range of technologies that the student could choose from, including biofeedback for hyperventilation technologies, sensors of ground position and texture fed back to hand worn technologies for balance control, sensors that align the semi-circular canal with gravity for more effective particle repositioning manoeuvres (for BPPV). This project would test the effectiveness of one or more of these technologies in clinical populations

Professor Patrick Chinnery (pfc25@medschl.cam.ac.uk) – Neurology

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:

Mitochondrial DNA Mutations and Human Disease (also with Dr Rita Horvath)

Mutations of mitochondrial DNA (mtDNA) are a major cause of inherited diseases and contribute to neurodegeneration. Many are heteroplasmic, with a mixture of mutated and wild-type genomes. Differences in the proportion of heteroplasmy in different tissues determines the severity of disease, but the mechanisms responsible are not 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. Similar mechanisms are also involved in determining how mutations accumulate in the brain during life. The aim of this project is to define the key mechanisms that explain how heteroplasmy changes during life using state-of-the art approaches including human stem cell models (iPSCs), single-cell genomics and transcriptomics. Ultimately, we aim to discover a way to prevent mtDNA mutations from accumulating in the brain, leading to new treatments for neurodegenerative disorders.

Discovering new Neurogenetic Diseases (also with Dr Rita Horvath)

We play a leading role in the Genomics England – Neurology Genomics Clinical Interpretation Partnership and the MRC International Centre for Neuromuscular Disorders. Both involve the analysis of whole genome sequence data from over >1000 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 Role of Nuclear-Mitochondrial Cross-Talk in Disease (also with Dr Rita Horvath)

Emerging evidence implicates disrupted cross-talk between the cell nucleus and the mitochondrion in both inherited diseases and common late-onset multifactorial disorders including Alzheimer’s and Parkinson’s disease. Using a combination of genomic and cell biology techniques, and unbiased CRISPR-Cas9 screens, this project will determine how the mitochondrion communicates with the cell nucleus, and how this is disrupted in human diseases. The ultimate aim is to harness this knowledge to develop new treatments acting through this novel mechanism.

References

Wei W, Tuna S, Keogh MJ, Smith KR, Aitman TJ, Beales PL, Bennett DL, Gale DP, Bitner-Glindzicz MAK , Black GC, Brennan P, Elliott P, Flinter FA, Floto RA, Houlden H, Irving M, Koziell A, Maher ER, Markus HS, Morrell N, Newman WG, Roberts I, Sayer JA, Smith KGC, Taylor JC, Watkins H, Webster AR, Wilkie AO, Williamson C, on behalf of the NIHR BioResource – Rare Diseases and the 100,000 Genomes Project – Rare Diseases Pilot, Ashford S, Penkett CJ, Stirrups KE, Rendon A, Ouwehand WH, Bradley JR, Raymond FL, Caulfield M, Turro E, Chinnery PF. Germline selection shapes human mitochondrial DNA diversity. Science 2019: 2019 May 24;364(6442). PMID: 31123110

Keogh MJ, Wei W, Aryaman J, Walker L, van den Ameele, Coxhead J, Wilson I, Bashton M, Beck J, West J, Chen R, Haudenschild C, Bartha G, Luo S, Morris CM, Jones NS, Attems J, Chinnery PF. High prevalence of focal and multi-focal somatic genetic variants in the human brain. Nature Communications 2018 Oct 15;9(1):4257. PMID:30323172

Floros VI, Pyle A, Dietmann S, Wei W, Tang WWC, Irie N, Payne BAI, Capalbo A, Noli L, Coxhead J, Hudson G, Crosier M,Strahl H, Khalaf Y, Saitou M, Ilic D, Surani MA, Chinnery PF. Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos. Nature Cell Biology 2018 Feb;20(2):144-151. PMID: 29335530 Also see: News and Views, Nature Cell Biology 2018;20:118-126

Professor Marek Czosnyka (mc141@medschl.cam.ac.uk ) – 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.

Dr Rita Horvath (rh732@medschl.cam.ac.uk) – Neurology

Studying the Molecular Mechanism of Mitochondrial Aminoacyl tRNA Synthetases in Neurons

(Co-supervised by Professor Patrick Chinnery)

Aminoacyl-tRNA synthetases (ARSs) are essential and ubiquitous ‘house-keeping’ enzymes responsible for charging amino acids to their cognate tRNAs and provide the substrates for global protein synthesis in the cytosol and mitochondria. Mutations in each of the 19 human mitochondrial and many of the cytosolic ARS genes have been reported in human disease. Glycyl- (GARS) and lysyl tRNA (KARS) synthetase genes encode both cytosolic and mitochondrial ARS enzymes, suggesting links between protein syntheses in these two distinct cellular compartments. Despite being ubiquitously expressed, mutations in these genes show an unexpected variety of phenotypes, including many neurological disorders affecting the white matter, causing epileptic encephalopathy, pontocerebellar hypoplasia, peripheral neuropathy or intellectual disability, while other characteristic phenotypes affect other organs. The cause of the selective vulnerability, or the exact molecular mechanisms leading to such tissue specific clinical manifestations are poorly understood.

In human cells, two distinct groups of ARSs encoded by separate genes can be distinguished by their cytoplasmic or mitochondrial localization however, GARS (glycyl tRNA synthetase) and KARS (lysyl tRNA synthase) are bi-functional enzymes functioning in both mitochondrial and cytosolic translation. This project focuses on the molecular mechanism of tissue specific manifestations in mitochondrial and bi-functional tRNA synthetase-associated mutations by investigating substrates and signalling pathways involved in the protein translation axis. We use human neuronal cell lines derived from patient fibroblasts to model the defect in neurons. Furthermore, ARSs have been described to have non-canonical functions which will be further investigated by identifying new binding partners.

References

D’Souza AR, Minczuk M. Mitochondrial transcription and translation: overview. Essays Biochem. 2018 Jul 20;62(3):309-320.

Boczonadi V, Ricci G, Horvath R. Mitochondrial DNA transcription and translation: clinical syndromes. Essays Biochem. 2018 Jul 20;62(3):321-340. Print 2018 Jul 20. Review.

Boczonadi V, Meyer K, Gonczarowska-Jorge H, Griffin H, Roos A, Bartsakoulia M, Bansagi B, Ricci G, Palinkas F, Zahedi RP, Bruni F, Kaspar B, Lochmüller H, Boycott KM, Müller JS, Horvath R. Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons. Hum Mol Genet. 2018 Jun 15;27(12):2187-2204.

Boczonadi V, Jennings MJ, Horvath R. The role of tRNA synthetases in neurological and neuromuscular disorders. FEBS Lett. 2018 Mar;592(5):703-717.

New Genomic Approaches to Explore the Neurogenetic Disease Burden of Consanguineous Marriages

(Co-supervised by Professor Patrick Chinnery)

This project aims to determine the burden of inherited neurogenetic conditions in consanguineous marriages in Turkey and thereby develop and improve genetic diagnosis and understanding of severe and chronic disorders in childhood affecting primarily the brain, the nervous system and skeletal muscle.

Expert paediatric neurologists in Turkey carried out detailed clinical investigations of around 250 children from consanguineous families with severe childhood disorders of the brain, nervous system or muscle and obtained blood and skin biopsy samples from these children as well as their unaffected parents and affected or unaffected siblings. DNA has undergone whole exome sequencing followed by in-depth computer analysis. Potential genetic causes in relevant genes have been identified and will be further explored to establish their function and prove whether these varaints are indeed the cause of the child’s condition.

The scientific work will be carried out in this project and involves bioinformatics analysis of exome datasets as well as the use of stem cell technology to transform skin cells into nerve cells. We also perform genetic manipulations in zebrafish embryos to model the genetic defect and to better understand the function of the gene in the nervous system. Exploring these aspects in human cells and fish allows research towards the development of targeted and effective treatments for these diseases in humans. In addition to the expected discovery of new disease-causing genes, we will also generate and share valuable data on consanguineous families in Turkey, which will help to understand the impact of consanguinity on severe childhood disorders in populations with high consanguinity rates.

References:

Burns DT, Donkervoort S, Müller JS, Knierim E, Bharucha-Goebel D, Faqeih EA, Bell SK, AlFaifi AY, Monies D, Millan F, Retterer K, Dyack S, MacKay S, Morales-Gonzalez S, Giunta M, Munro B, Hudson G, Scavina M, Baker L, Massini TC, Lek M, Ying Hu Y, Ezzo D, AlKuraya FS, Kang PB, Grifin H, Foley R, Schuelke M, Horvath R*, Bönnemann CG. Variants in EXOSC9 disrupt the RNA exosome and result in cerebellar atrophy with spinal motor neuronopathy. Am J Hum Genet 2018 May 3;102(5):858-873.

Bansagi B, Griffin H, Whittaker RG, Antoniadi T, Evangelista T, Miller J, Greenslade M, Forester N, Duff J, Bradshaw A, Kleinle S, Boczonadi V, Steele H, Ramesh V, Franko E, Pyle A, Lochmüller H, Chinnery PF, Horvath R. Genetic heterogeneity of motor neuropathies. Neurology 2017;28;88(13):1226-1234.

Boczonadi V, Müller V, Pyle A, Munkley J, Dor T, Quartararo J, Ferrero I, Karcagi V, Giunta M, Polvikoski T, Birchall D, Princzinger A, Cinnamon Y, Lützkendorf S, Piko H, Reza M, Florez L, Santibanez-Koref M, Griffin H, Schuelke M, Elpeleg O, Kalaydjieva L, Lochmüller H, Elliott DJ, Chinnery PF, Edvardson S and Horvath R. EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia. Nat Commun 2014;5:4287.

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 GS, Turnbull DM, Ramesh V, Santibanez-Koref M, McFarland R, Horvath R, Chinnery PF. Whole exome sequencing defines the genetic basis of multiple mitochondrial respiratory chain complex deficiency. JAMA 2014;312:68-77.

What Causes Tissue Specific Phenotypes in Mitochondrial Disease?

(Co-supervisors: Professor Patrick F. Chinnery, Dr. Michal Minczuk)

Most inherited mitochondrial diseases are caused by abnormal mitochondrial translation. However, despite having a common molecular basis, patients often have strikingly distinct tissue-specific phenotypes that are poorly understood. There is increasing evidence that regulation of post-transcriptional modifications of mt-tRNAs (epitranscriptome) is finely tuned for the control of mitochondrial gene expression which varies in different tissues.

We will investigate the regulation of mt-tRNAs in affected and unaffected cell types of patients carrying heteroplasmic and homoplasmic mt-tRNA mutations or mutations in nuclear genes involved in mitochondrial translation. These studies will reveal the relative stoichiometry of modifications in the mt-tRNA pool and help explain its relevance to human disease. We will analyse RNA levels in patient derived skin cells and will transform them into neuronal and other cell types. We will determine which RNA species are modified in the different cell types. We expect to find that the cellular and metabolic characteristics of different tissues influence mitochondrial tRNA modifications and potentially drive the segregation of mtDNA mutations.

We anticipate that common pathways will emerge, linking and informing the different defects of mitochondrial translation, providing a comprehensive understanding of important mechanisms contributing to tissue specificity. We aim to identify fundamental mechanisms that have broader relevance for understanding tissue and organ selectivity in other disorders where mitochondrial dysfunction plays a key role. It is likely that these pathways will provide novel therapeutic targets for mitochondrial diseases.

References:

Boczonadi V, et al., Horvath R. Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons. Hum Mol Genet. 2018;27(12):2187-2204

Taylor RW, Pyle A, Griffin H, et al., Horvath R, Chinnery PF. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA. 2014;312(1):68-77.

Boczonadi V, Jennings MJ, Horvath R. The role of tRNA synthetases in neurological and neuromuscular disorders. FEBS Lett. 2018;592(5):703-717

Richter U, et al. RNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis. Nat Commun. 2018;9(1):3966.

Boczonadi V, Ricci G, Horvath R. Mitochondrial DNA transcription and translation: clinical syndromes. Essays Biochem. 2018;62(3):321-340.

Professor Hugh Markus (hsm32@medschl.cam.ac.uk) – Neurology

Does Histone Deacetalyse Inhibition Reduce Atherosclerosis and Stroke Risk (PhD only) 

The Cambridge Stroke Group led the identification of the HDAC9 (histone deacetalyse 9) gene as a risk factor for stroke. The association is specific for large artery stroke due to atherosclerosis. Further studies have shown increased expression of HDAC9 in the carotid artery plaque, and that reducing HDAC9 expression reduces stroke risk in animal models. Sodium valproate, which is a widely used antiepileptic, is an HDAC inhibitor. In large epidemiological datasets we have shown that sodium valproate is associated with reduced stroke risk, compared with other antiepileptics. We are now investigating, in a phase 2 randomised controlled trial design, whether sodium valproate reduces cerebral atherosclerosis via HDAC inhibition.

The project will involve studying the effect of sodium valproate on imaging markers of atherosclerosis including both structural markers (CT/MRI) to look at the volume and type of the atherosclerotic plaque, and positron emission tomographic (PET) markers to look at plaque activation/inflammation. The study would involve patient contact with recruiting and scanning patients. The student would gain experience in clinical research and clinical trial methodology, as well as both performing and analysing brain imaging.

What causes Lacunar Stroke? (PhD only)  

Lacunar stroke occurs due to blockage of the small blood vessels in the brain (cerebral small vessel disease). It accounts for 25% of all strokes, and is the major pathology underlying vascular dementia. Despite its importance we understand relatively little about its pathophysiology. The studentship will involve using unique datasets to determine risk factors for, and gain insights into, the pathogenesis of cerebral small vessel disease. These include data from DNA Lacunar 1 and DNA Lacunar 2 (>2000 patients with MRI confirmed lacunar stroke), as well as using the imaging cohort within UK Biobank to look at MRI markers of small vessel disease in the normal population (currently 25 000, increasing to 100 000 participants). The project could focus on traditional epidemiological methodology to look at risk factors, and/or genome wide association study data and sequencing data to look at genetic risk factors. The student would use this information to help prioritise potential treatment approaches to target this important disease. The project would provide training in clinically applied research, and statistical approaches applied to both epidemiological and/or genetic datasets.

What Causes Apathy and Fatigue in Cerebral Small Vessel Disease? (PhD only)

Cerebral Small Vessel Disease (SVD) causes a quarter of all strokes and is the most common cause of vascular dementia and vascular cognitive impairment. Recently the importance of behavioural symptoms such as apathy and fatigue in SVD has been recognised. These present a major burden for patients and their families.

SVD causes damage to the white matter and increasing evidence suggests that disruption of distributed networks relying on the integrity of white matter tracts may underlie the genesis of both apathy and fatigue. White matter ultrastructural damage, and damage to specific white matter tracts, can be studied using magnetic resonance imaging (MRI), with diffusion tensor imaging (DTI). In previous studies we have shown that damage to white matter networks underlies apathy in SVD (Hollocks et al 2016). In this project, the student will take these studies further to investigate the relationship of apathy, and specific subcomponents of apathy, as well as fatigue, to white matter damage.

The project will study a group of patients with pure white matter damage occurring at an earlier age (due to a monogenic form of SVD called CADASIL) using this as a model of pure SVD; this overcomes a common problem in studying the elderly in that most elderly people have concurrent neurodegenerative and vascular pathology. The student will recruit patients from the National CADASIL clinic which is run in Cambridge (www.cadasil.co.uk). The project will provide the student with expertise in a variety of state of the art MRI imaging techniques primarily based on DTI, including voxel-symptom mapping, tractography, and structural network analysis. The project will also provide experience in cognitive and behavioural testing. It would suit a Psychologist or Neuroscientist with an interest both in working with patients, and in performing MR image analysis.

Reference: Hollocks MJ, Lawrence AJ, Brookes RL, Barrick TR, Morris RG, Husain M, Markus HS. Differential relationships between apathy and depression with white matter microstructural changes and functional outcomes. Brain. 2015 Dec;138(Pt 12):3803-15.

Developing a New Model for Vascular Stroke using Human Induced Pluripotent Stem Cells (hiPSC) with the HDAC9 Risk Genetic Variant (PhD only)  

(Co-supervised by Dr Alessandra Granata) 

A quarter of all stroke is classified as large artery stroke, most of which are attributed to atherosclerosis. Together with conventional risk factors, there is evidence that a strong heritable genetic component contributes to large artery stroke risk.

In 2012, the Cambridge Stroke Research group published the first large genome wide study (GWAS) in ischaemic stroke, which identified a common variant in the Histone Deacetylase 9 (HDAC9) gene as the strongest genetic risk for large artery stroke to date. This offers the exciting possibility that inhibiting HDAC9 could prevent stroke. Consistent with this sodium valproate, a non-specific inhibitor of all HDACs, was found to be associated with lower stroke risk in human. However, the mechanisms linking this HDAC9 variant with increased stroke risk are still poorly understood. Better understanding these mechanisms, and also developing relevant models containing the generic variant is essential, if we are to translate this genetic finding into improved patient care.  

In the proposed project, the student will use hiPSC containing the HDAC9 genetic variant derived from skin biopsies from patients with large artery stroke to generate cell types of the large artery including smooth muscle cells, endothelial cells and macrophages, which will be co-cultured to mimic the atherosclerotic plaque environment. This model will be used to investigate:

1. How the variant influences HDAC9 regulation and which transcriptional factors are involved in controlling HDAC9 expression by performing chromatin-immunoprecipitation (ChIP) assay and gene reporter assay.
2. How the stroke variant affects the normal vascular cells functions in response to inflammation by performing a range of cell-based assay and omics analysis in stroke risk hiPSC-derived vascular cells and CRISPR-edited isogenic cells.
3. And to test new specific HDAC inhibitors, with the aim of uncover new mechanisms/targets for the treatment of large-vessel stroke.
4. References:

• 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).
• Markus, H. S. et al. Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis. Stroke. 44, 1220–5 (2013).
• Brookes, R. L. et al. Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack. Stroke 49, 54–61 (2018) Stroke is often thought as disease of the elderly but a quarter of all strokes occur in individual of working age. While stroke incidence is decreasing overall in westernised population, the incidence of stroke in younger individuals is not and remains an important health problem. This is because the causes of stroke in young adults are different from the ones in older individuals, where traditional risk factors like high blood pressure and cholesterol play a dominant role; thus no targeted clinical treatments are available.Monogenic SVD are caused by mutations in different genes that affect the small penetrating vessels in the brain. The molecular mechanisms underlying SVD are still largely unknown but emerging evidence suggests that these diseases are caused by dysregulation of the extracellular matrix (ECM) proteins and ECM associated-pathways, which in turn causes the disruption of the blood brain barrier (BBB).We hypothesise that the two most common forms of monogenic SVD, CADASIL, caused by mutations in the transmembrane receptor NOTCH3 and CARASIL, caused by mutations in the serine protease HTRA1, converge in common pathways, involving the disruption of the ECM, leading to BBB breakdown, which may contribute to the vessel degeneration in SVD. In the proposed study, the student will use induced pluripotent stem cells (hiPSC) derived from patients with CADASIL and CARASIL to:
• The BBB has the important function of regulating the exchange between the blood and the brain and is made up of three cellular components, brain endothelial cells, mural cells and astrocytes, and the basal lamina/ECM that support them.
• Genetic risks, driven by abnormalities in single genes, are also known to play an important role in early on-set stroke and by far the most common type of genetic stroke is Cerebral Small Vessel Disease (SVD).
• (Co-supervised by Dr Alessandra Granata)
• Investigating CADASIL and CARSIL Shared Molecular Mechanisms of the ECM in a Human Blood Brain Barrier Model to Understand the Causes of Early-Onset Stroke. (PhD only)

1. Develop an in vitro human model of the blood brain barrier by using a 3D co-culture microfluidic system that mimics the physiological features of the BBB.
2. Identify common pathological pathways by performing proteomic analysis on the ECM extracted from these SVD 3D co-cultured models.
3. Set up a drug-screening platform using the SVD hiPSC-derived BBB in vitro model to identify potential new drugable targets for the prevention and cure of stroke.

References:

• Tan, R., Traylor, M., Rutten-Jacobs, L. & Markus, H. New insights into mechanisms of small vessel disease stroke from genetics. Clin. Sci. 131, 515–531 (2017).
• Zellner, A. et al. CADASIL brain vessels show a HTRA1 loss-of-function profile. Acta Neuropathol. 136, 111–125 (2018).
• Campisi, M. et al. 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials 180, 117–129 (2018).

Does Brain Network Disruption Secondary to White Matter Track Disruption Underlie Apathy after Stroke? (PhD Only)

Apathy is a common consequence of stroke. It is a particular feature of small vessel stroke which results in damage to the white matter and deep grey matter nuclei resulting in disruption of complex brain networks dependent on white matter tract integrity. Using brain network analysis, derived from MRI diffusion tensor imaging tractography, we have shown that apathy is associated with disruption to large scale brain matter networks including the reward networks. We have developed a novel model of apathy in stroke, in which it can result either from direct damage to network hubs, or remote damage which disrupts network hubs via propagation within networks. The studentship will follow up this work to further investigate the neurobiological basis of apathy in stroke using MRI analysis (including DTI and structural networks) as well as neuropsychological assessment.  The eventual aim is to use better understanding of why apathy occurs in individual patients, to develop targeted treatment approaches. The student will work on an existing dataset of patients recruited with acute stroke and followed up for one year, to determine how apathy influences outcome, as well as advanced imaging datasets in cerebral small vessel disease. The project would suit a student with an interest in psychology and/or cognitive neuroscience. It would provide training in MRI including advanced data analysis, and analysis of cognitive data. There would be opportunities for patient interaction if wished.

Key References:

1: Tay J, Tuladhar AM, Hollocks MJ, Brookes RL, Tozer DJ, Barrick TR, Husain M, de Leeuw FE, Markus HS. Apathy is associated with large-scale white matter network disruption in small vessel disease. Neurology. 2019 Mar12;92(11):e1157-e1167.

2: Hollocks MJ, Lawrence AJ, Brookes RL, Barrick TR, Morris RG, Husain M, Markus HS. Differential relationships between apathy and depression with white matter microstructural changes and functional outcomes. Brain. 2015 Dec;138(Pt 12):3803-15.

Dr Stefano Pluchino (spp24.cam.ac.uk) – Neurology

Website;  www.pluchinolab.org

Making Induced Neural Stem Cells from People with Progressive Multiple Sclerosis

(co-supervised with Alexandra Nicaise)

Multiple sclerosis (MS), an immune-mediated disease of the central nervous system, afflicts an estimated 2-3 million people worldwide, most of whom will ultimately develop a progressive form of the disease with few therapeutic options. In this project we aim to develop the capability to generate clinical grade, patient-specific induced neural stem cells (iNSCs) from people with progressive MS (PMS). Somatic cells have been reprogrammed to stably expandable iNSCs and will be differentiated and monitored for several makers of pluripotency/multipotency, checked for morphological, function and genomic stability. The long-term goal of this project will be to evaluate the safety and therapeutic potential of iNSCs from people with PMS in anticipation for use in clinical trials.

Modelling Cellular Senescence in Primary Progressive Multiple Sclerosis with Neural Stem Cells

(co-supervised with Alexandra Nicaise)

Primary progressive multiple sclerosis (PPMS) is a chronic demyelinating disease of the central nervous system, which currently lacks restorative therapies. Transplantation of neural stem cells (NSCs) has been shown to promote healing of the injured CNS, but previous work has demonstrated that NSCs from patients with PPMS are prematurely senescent. Cellular senescence causes a pro-inflammatory cellular phenotype that impairs tissue regeneration. Senescence in PPMS NSCs was found to be associated with increased secretion of HMGB1, a pro-inflammatory alarmin found to inhibit oligodendrocyte differentiation, and also found increased within white matter lesions of PPMS autopsy tissue. This project aims to understand the role of HMGB1 in PPMS NSC senescence using techniques such as CRISPR-Cas9, RNA sequencing, and functional NSC assays. The long-term goal of this project will be to determine the cause of senescence in NSCs from patients with PPMS and if these cells are suitable for therapeutic use.

Single-cell RNAseq Analysis of Reactive Astrocyte Heterogeneity in Spinal Cord Injury (SCI)

(co-supervised with John Marioni)

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.

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.

Single-cell RNAseq Analysis of Non-Neuronal Cell Heterogeneity in Experimental Autoimmune Encephalomyelitis (EAE)

(co-supervised with John Marioni)

Multiple sclerosis (MS) is characterized by distinct disabilities in voluntary movement, cognition, and vision. Investigations of cell types in experimental autoimmune encephalomyelitis (EAE) have shown that non-neuronal cells have varying gene expression depending on the cell type and region. However, the heterogeneity within cell types in EAE models have yet to be characterized. The aim of this project is to investigate the heterogeneity within non-neuronal cell types in EAE at unprecedented depth by employing the novel, unbiased technology of ex vivo single-cell RNA sequencing to obtain high-throughput gene expression profiling.

These results are expected to ultimately lead to the identification of novel therapeutic targets for future molecular approaches with significant translational value in chronic neuroinflammatory conditions, including multiple sclerosis, and the potential to compare and contrast with other reactive non-neuronal profiles in the future.

The Metabolic Determinants of Chronic Neuroinflammation

(co-supervised with Luca Peruzzotti-Jametti)

Despite the absence of clinically relevant immune-related attacks, a diffuse activation of the immune system is one of the major drivers of disease progression in Multiple Sclerosis (MS). However, differently from relapsing remitting MS, in progressive MS the immune cells that mediate the damage are called mononuclear phagocytes (MPs).

MPs 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 MPs undergo a “metabolic switch” in chronic neuroinflammation that makes them more active and deleterious.

The goal of this project is to understand how the different types of mononuclear phagocytes (resident microglia and infiltrating macrophages) change their metabolism in the experimental autoimmune encephalomyelitis (EAE) mouse model of neuroinflammation. To achieve this aim, we will use a combination approach based on FACS sorting, untargeted metabolomic via LC-MS, seahorse analysis and gene expression profiling in both WT and relevant transgenic mice.

The results of this project are expected to lead to the identification of novel ways to modulate the metabolism of innate immune cells to treat chronic neuroinflammation.

SUCNR1/GPR91 Signalling in Mononuclear Phagocytes

(co-supervised with Luca Peruzzotti-Jametti)

We have previously demonstrated that several metabolites change in the cerebrospinal fluid (CSF) of mice with chronic neuroinflammation. Among these, we found that the TCA cycle intermediate succinate accumulates in the CSF of mice and its accumulation is linked with the activation of the innate immune system.

We hypothesise that succinate is a paracrine signal that maintains chronic neuroinflammation acting as an alarmin that locally activates the succinate receptor SUCNR1/GPR91 on mononuclear phagocytes (MPs) to initiate and exacerbate compartmentalised immune responses.

Within this project, we will investigate the role of SUCNR1/GPR91 in the pathogenicity of bone marrow-derived CNS infiltrating Ccr2+ macrophages and locally recruited Cx3cr1+ microglial cells in experimental autoimmune encephalomyelitis (EAE), taking advantage from state-of-the-art Sucnr1flox tg mice. We will also develop new ways to antagonise SUCNR1/GPR91 signalling in vivo using in-house state-of-the-art pRNA nanotherapeutic-based delivery of Sucnr1 siRNAs-

Identifying the main cellular and molecular events elicited by succinate, as a metabolic signal in chronic neuroinflammation, and targeting these events in MPs, is an extremely exciting prospect that will allow us to impact on many CNS diseases, including Multiple Sclerosis (MS).

Understanding the Role of Mitochondria in Neuroinflammation

(co-supervised with Luca Peruzzotti-Jametti)

The differentiation of immune cells into distinct phenotypes involves specific metabolic signatures and complex changes in mitochondria. Inflammatory cells mostly display a dysfunctional mitochondrial respiratory chain, and a broken Krebs cycle. This interrupted TCA cycle turns mitochondria into toxic factories where several metabolic intermediates with important signalling functions accumulate and are implicated in influencing immune cell phenotype and function.

This project aims at providing high-dimensional, single-cell analysis, of mitochondria in inflammatory cells from the experimental autoimmune encephalomyelitis (EAE) mouse model of Multiple Sclerosis (MS) and from post-mortem MS cases. To this aim, we will adopt the Hyperion™ Imaging System, which brings together high-parameter CyTOF™ technology with imaging capability, as well as morphological analyses of immune cells via electron microscopy. The goal of this project is to unravel novel pathways that regulate mitochondrial function in immune cells to develop new diagnostic and therapeutic tools for MS.

Dr Chris Rodgers (ctr28@cam.ac.uk) – WBIC

Ultra-High Field (7T) Magnetic Resonance Imaging (MRI) Development (PhD only)

I founded a new ultra-high field (7T) MRI physics group in Cambridge in autumn 2017. We develop cutting-edge methods for studying the human brain and body using Cambridge’s state-of-the-art Siemens Terra 7T MRI scanner. My group have active collaborations with clinicians in clinical neurosciences, psychiatry, oncology, and cardiology (Papworth), and with experts in cognitive neuroscience. I welcome PhD students to join the group. The following are areas of strong interest from our community, which would be suitable to develop a PhD project in discussion with me.

(i) Developing new spectroscopic imaging pulse sequences to map neurochemical profiles across the whole brain in a single scan. We have hardware available to apply these methods to study metabolites containing 1H (e.g. NAA, creatine, GABA, GSH) or 31P (e.g. PCr, ATP, in vivo pH mapping) or 13C (e.g. labelled glucose or succinate).

(ii) Developing new methods for neuroimaging, particularly for imaging blood flow in small vessel disease, or for rapid, motion-corrected fMRI in deep brain nuclei.

(iii) Developing new metabolic imaging methods for use in the human body. These would use a new multinuclear (¹H and ³¹P) whole-body coil being built for me by Tesla Dynamic Coils (Netherlands). This could be developed in collaboration with colleagues at Papworth and Radiology for studies in the heart.

(iv) Imaging of metabolism by 2H deuterium metabolic imaging (DMI). This is a promising new technique that may compete with 18FDG-PET, but without radiation. We are developing this for use in humans at 7T.

We look for students with strong maths skills, and ideally programming experience in C/C++, python or Matlab (or a willingness to learn), or with RF engineering skills. Most of my group have a physical science or engineering background. You will receive extensive training in biomedical imaging.

If you are interested in these projects or other aspects of 7T MRI physics development, please email ctr28@cam.ac.uk and I will be happy to discuss the details with you.

Professor James Rowe (james.rowe@mrc-cbu.cam.ac.uk) – Neurology

Progression in Neurodegenerative Tauopathies: Neuroimaging Biomarkers and Disease Models (Co-supervised by Dr Timothy Rittman)

One of the challenges in understanding neurodegenerative disorders is to relate the effect of genetic and molecular changes associated with disease to the level of the whole brain. Increasing evidence points towards the vulnerability of macro-scale brain networks in the progression of neurodegeneration. In order to investigate disease progression in brain networks, this project in the Cambridge Centre for Parkinson Plus will examine changes in structural networks in tau associated neurodegenerative diseases. These scans are drawn from a cohort study of people with the primary tauopathies of Progressive Supranuclear Palsy, Corticobasal Degeneration and Frontotemporal Dementia. Imaging data will be enriched with information available from post-mortem tissue to anchor the models in neuropathological changes, and with clinical cognitive data to gauge the influence of structural changes on clinical syndromes. There may be opportunities to extend this work with multimodal imaging techniques such as functional MRI. The successful candidate will use structural imaging techniques such as Diffusion Tensor Imaging and cortical thickness analysis (freesurfer) to understand the progression of tau associated neurodegenerative pathology through the brain. The candidate will build computational models that can be used to test hypotheses of tau spread and regional susceptibility. A familiarity with coding languages is essential and some experience of neuroimaging analysis is highly desirable.

The project will be co-supervised by Dr Timothy Rittman, a clinician scientist with extensive experience in neuroimaging applied to neurodegenerative diseases and genetics. This project supports the wider work of the Cambridge Centre for Parkinson’s Plus (https://ccpp.cam.ac.uk/)

Bridging the Gap in Frontotemporal Dementia: From Cell to Cognition

Your PhD will work across models of brain disease and human brain imaging (MEG), to understand the mechanisms of action of candidate drug treatments for frontotemporal dementia. You will validate these models of human brain function with spectroscopy, neuropathological data or PET measurements of synapse density.

One of the major challenges in dementia research is how to harness rapid advances in cell and molecular knowledge of disease to understand the human patient syndrome, and to treat it better. Frontotemporal dementia is a common young-onset dementia, with dramatic changes in behaviour and language.  It is strongly genetic, and has focal changes in frontal and temporal cortex, which can be described will molecular and cellular precision. Our group at the Centre for Frontotemporal Dementia (ftd.neurology.cam.ac.uk) has developed detailed models of cortical microcircuits, that can generate evoked electromagnetic responses that match magnetoencephalographic recordings. Our senior post doctoral team and world-class facilities for brain imaging and informatics will ensure the success of an innovative and impactful PhD in translational neuroscience.

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 Emmanuel Stamatakis (eas46@cam.ac.uk) – Anaesthesia

 https://sites.google.com/site/ccigcambridge/

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 Jelle van den Ameele (jv361@cam.ac.uk) Neurology and Mitochondrial Biology Unit

Role of the neural stem cell niche in vulnerability to mitochondrial dysfunction (PhD preferable)

Mitochondrial diseases are caused by defects in genes required for oxidative phosphorylation (OxPhos) and mitochondrial ATP production. Not all organs are equally susceptible to mitochondrial disease, which suggests that some tissues may have buffering mechanisms to maintain normal functionality, despite problems in their energy production.

The objective of this project is to study whether interactions between different cell types, may render tissues more, or less vulnerable to mitochondrial disease.

The project will be focused on the developing Drosophila brain. We previously showed that neural stem cells in the Drosophila brain rely heavily on OxPhos (van den Ameele and Brand, eLife, 2019) and will now study how they interact with their stem cell niche. We take advantage of the powerful genetics of Drosophila and combine targeted genetic manipulations with confocal and super-resolution imaging, biosensors to perform in vivo metabolite measurements and innovative sequencing approaches to study how different cell-types within the post-embryonic brain of a living organism interact and respond to mitochondrial dysfunction.

I am a clinical neurologist and am currently starting a new group at the Mitochondrial Biology Unit. Our group will use a wide range of techniques and model systems, including embryonic stem cells (ESC), mouse and Drosophila to identify novel determinants of tissue-specific phenotypes of mitochondrial and neurodegenerative diseases. The results are potentially relevant for conditions like diabetes and cancer, where mitochondrial dysfunction is known to play a role too. Ultimately, I hope to uncover potential therapeutic targets to treat these disorders.

Dr Guy Williams (gbw1000@cam.ac.uk) WBIC

Modelling of Diffusion Weighted MRI

Recent methodological advances in diffusion weighted MRI allows for more complex modelling of anatomical parameters. There is interest in more pathologically meaningful metrics (such as axonal diameter measurements), those that more accurately reflect tissue complexity (such as kurtosis) and metrics that are robust and comparable across multi-centre studies. For such problems the optimal pulse sequences for such acquisitions are undetermined. This project will be to trial both different acquisition schemes and modelling, and apply these methods to clinically relevant research questions. The project will benefit from a research collaboration agreement with Siemens and access to both 3T and 7T field strength scanners for data acquisition. The project will be appropriate for a candidate with a background in Physics and strong mathematical skills, and an interest in translating methodology to provide novel and practical research tools.

Methods for Quantitative MRI

The contrast of magnetic resonance datasets is conventionally usually dimensionless; in order to derive meaningful quantitative measures (such as T1, T2, diffusion metrics etc) longer acquisitions and further modelling are required. However, for longitudinal studies and for multi-site studies (including different hardware platforms), repeatable and meaningful metrics are increasingly required (quantitative MRI; qMRI). This project is to study current strategies for robust qMRI including faster data acquisition and/or synthetic approaches. It will benefit from ongoing local longitudinal studies and the availability of multi-site datasets for comparison. The project will be appropriate for a candidate with a background in Physics and strong mathematical skills, and an interest in translating methodology to provide novel and practical research tools.

Alternative Analysis Strategies for Disorders of Consciousness Imaging Data

One of the most challenging clinical populations imaged within the Wolfson Brain Imaging Centre is that of patients with Disorders of Consciousness. The data from these participants is very valuable but also compromised by motion (for all data), and persistence of response (for functional data). Alternative methods are required to assess the information content of such datasets where participants cannot be assumed to follow task instructions. This project will be to use previously acquired data, potentially correlating with behavioural data from outside of the scanner, in collaboration with the Cambridge Research into Consciousness (CRIC) group. The project benefits from international collaborations funded through the McDonnell Foundation. The project will be appropriate for a candidate with a background in Physics/Maths/Statistics and strong mathematical/statistical skills.

Dr Caroline Williams-Gray (chm27@cam.ac.uk) – Neurology/John Van Geest Centre for Brain Repair

Investigating the Immune Basis of Parkinson’s Disease (PhD only)

It is now well established that immune activation occurs in Parkinson’s disease, but whether it plays a critical role in disease onset and progression remains uncertain. This is a critical question to address given that the immune system is a tractable target for disease-modifying therapy. My lab focuses on investigating this through neuropathological studies on post mortem human brain, PET brain imaging studies and analysis of blood and cerebrospinal fluid samples from Parkinson’s cases and controls. The project will extend this work to include investigation of cases with prodromal Parkinson’s disease, in order to determine whether immune activation precedes disease onset and whether it is predictive of conversion to Parkinson’s disease. It will focus on studying markers of immune activation and dysregulation in biological samples, and correlation with detailed longitudinal clinical measures and outcomes. Laboratory techniques will include multiplex immunoassays, immunophenotyping using flow cytometry, and functional lymphocyte and monocyte assays. This work will allow detailed characterisation of immune abnormalities in the earliest stages of PD to guide the development of future immune-based therapies and identify optimal immune-related biomarkers to track response to such therapies.