The Department of Clinical Neurosciences are encouraging applications despite the Covid pandemic, and we look forward to welcoming our new arrivals. There are no changes to our admission process for all arrivals or applicants.

Communications between supervisors and students will depend on the project and arrangements for this will be implemented. Procedures have already been put in place for all buildings with clear guidelines to follow to ensure a safe working environment, and some of our students are already back to work.

Further updates can be found here

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Applications for the Academic year October 2021- September 2022 open 2^nd September,  Funding deadlines are as follows:

Gates US: 14^th October 2020

Postgraduate Funding Competition (all other funders including Gates Cambridge): 3^rd December 2020

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 21, Lent 22 and Easter 22 are all being considered, but funding must already be secured, application 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 (PhD or MPhil)

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 (PhD or MPhil)

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 (PhD or MPhil)

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

Synthesis and evaluation of novel molecular imaging PET probes for imaging pathology related to COVID-19 (PhD or MPhil)

This project’s objective is to develop novel molecular PET imaging probes, that are selective to receptors linked to COVID-19 virus pathology, in particular in the brain. The project may involve  collaboration with researchers at Dept of Chemistry and University of Oxford. It will consist of 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 animal models using a high resolution PET scanner.

*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 signalling) 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 on this theme involve 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 and neuronal activity analyses e.g. calcium imaging (carried out in collaboration with optics physicists and computer scientists). Focused projects exploring benefits of modulation (e.g. induced degradation) of candidate ER-morphogens for neuronal health and axonal regeneration are also available.

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 the 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. The aggregation monitoring techniques include biochemical assays and microscopy-based techniques such as Fluorescence Lifetime Imaging. The interplay between cellular stress, its response and protein aggregation handling is also explored.

Endoplasmic Reticulum Associated ROS and Redox Dynamics in Neurons 

Reactive Oxygen Species (ROS) are utilised 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 the physiological and controlled supply of certain ROS and may also act as 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 utilising (and further development) of genetically encoded probes for live-cell redox and ROS imaging in genetically and pharmacologically manipulated neurons.

Dr Gabriel Balmus (gb318@cam.ac.uk) – UK Dementia Research Institute

Senescent cells exhibit a phenotypic shift, known as the senescence-associated secretory phenotype (SASP). The cytokine profile of SASP varies based on factors such as the cell type and inducer of senescence, but frequently SASP includes secretion of matrix metalloproteinases, reactive oxygen species, and cytokines such as IL-1β, TNFα, and IL-6 [1]. Through SASP, senescent cells contribute to the chronic sterile inflammation observed in aging known as “inflammaging,”  and can induce senescence in a paracrine manner to nearby cells [2]. In neurodegenerative diseases, SASP promotes disease progression through activating nearby glia and directly inducing apoptosis in neuronal cells [3, 4]. Critically, clearance of senescent cells in mouse models, either by senolytics or cell programming, can extend lifespan and ameliorate cognitive decline [5-8]. This further emphasizes the potential of senescence-targeted therapies. Despite their longevity and the absence of an ageing phenotype until late in life, the naked mole rat (NMR) displays the same types of cellular senescence found in a short-lived rodents and humans including the acquisition of SASP [9]. However, in contrast to mice and humans, senescence-related markers remain stable during NMR ageing [4, 10]. In humans, increased oxidative stress can be both cause and consequence of SASP [11]. Upon induction of senescence by irradiation, the NMR exhibits a greater upregulation of the oxidative stress response, compared to the increased apoptosis observed in the mouse [9]. This suggests NMR cells might have a mechanism for mitigating the non-cell autonomous induction of senescence promoted by SASP and other inducers of cellular senescence. Previous studies have shown the Alzheimer’s (AD) associated protein amyloid-beta (Ab) induces cellular senescence in astrocytes and oligodendrocytes [8, 12]. Interestingly, the NMR has levels of Ab similar to transgenic mouse models of AD, however they do not experience cognitive decline and in fact have higher levels of adult neurogenesis [13, 14]. Since previous studies indicate that the NMR’s longevity is not due to eliminating the process of cellular senescence, it is of interest to determine how the NMR SASP differs from the mouse and human. The composition of SASP and phenotypic alterations of senescent cells in the NMR brain are almost entirely unknown. Investigating the mechanism underlying NMR resistance to cellular senescence and the non-cell autonomous effects of SASP could potentially provide a novel therapeutic target for the treatment of age-related diseases like AD.

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

Identifying Novel disease Genes in Patients with Hereditary Motor Neuropathies

Charcot-Marie-Tooth disease (CMT) is a group of inherited disorders of the peripheral nerves. Clinical diagnosis of CMT can be made fairly accurately, and the clinical classification is very helpful in the identification of new disease genes. All types of CMT thought to affect approximately 5 to 40 per 100,000 individuals. We have recently re-evaluated the prevalence of CMT in Northern England, which is compatible with other European countries. Thus far more than 80 genes have been implicated in CMT, and the recent next generation CMT panel screening enable the mutation detection in all known rare neuropathy genes. However, achieving a genetic diagnosis is still challenging in some forms of inherited neuropathies, including hereditary motor neuropathies (~40% detection rate).

We have already characterized the clinical presentation and electrophysiology in over 100 patients with hereditary motor neuropathy. CMT panel and whole exome sequencing has been performed in genomic DNA samples of these patients and the confirmation of the exome results by Sanger sequencing is currently ongoing. We have recently reported a novel disease gene SYT2, which is the first gene involved in motor neuropathy affecting synaptic transmission and the involvement of the neuromuscular junctions raised the possibility of a novel approach for therapy.  This project will focus on genetic analysis of the exome results in hereditary motor neuropathies with the potential to identify further novel human disease genes. The evaluation of detected changes and the confirmation of pathogenicity may require further laboratory techniques, such as tissue culture studies, cDNA analysis and functional studies. We will explore the involvement of neuromuscular junction in the development of the neuropathy and will study whether the modification of the neuromuscular junction can be beneficial for these patients.

References:

1. Reilly MM, Shy ME. Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry 2009;80:1304-14.
2. Foley C, Schofield I, Eglon G, Bailey G, Chinnery PF, Horvath R. Charcot-Marie-Tooth Disease in Northern England. J Neurol Neursurg Psychiatry 2012;83:572-3.
3. 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 Mar 28;88(13):1226-1234.
4. Herrmann DN, Horvath R, Sowden JE, Gonzales M, Sanchez-Mejias A, Guan Z, Whittaker RG, Almodovar JL, Lane M, Bansagi B, Pyle A, Boczonadi V, Lochmüller H, Griffin H, Chinnery PF, Lloyd TE, Littleton JT, Zuchner S. Synaptotagmin 2 mutations cause an autosomal-dominant form of Lambert-Eaton Myasthenic Syndrome and non-progressive motor neuropathy.

New Genomic Approaches to explore the Neurogenetic Disease burden of Consanguineous Marriages

(Co-supervisor: Prof. 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 variants 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:

1. 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.
2. 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.
3. 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.
4. 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.

Targeting the Cellular Metabolism to treat Tissue-Specific Mitochondrial Diseases

(Co-supervisor: Prof. Patrick Chinnery and Dr. Juliane Müller)

Although mitochondria are present in almost all eukaryotic cell types, mitochondrial diseases have distinct tissue-specific phenotypes that are poorly understood. Our project focuses on mitochondrial diseases characterised by impaired mitochondrial translation, which can be caused either by mtDNA mutations (often in mt-tRNAs) or in nuclear encoded proteins that play a role in mitochondrial translation. Mt-tRNA or nuclear gene mutations affect tRNA levels and structure directly or indirectly, leading to a defect of mitochondrial protein synthesis. These mutations can also lead to the presence of free tRNAs without their cognate amino acid (‘uncharged tRNA’), which constitutes a stress signal for cells.

We will investigate whether different tissues have different levels of uncharged tRNAs and whether this correlates with the vulnerability for mitochondrial defects. Uncharged tRNA activates the integrated stress response (ISR), a major signalling pathway that allows eukaryotic cells to sense stress and adapt to it. We obtained fibroblasts from patients with different mitochondrial translation defects to determine tRNA and ISR levels. We will reprogram the fibroblasts to iPSCs and differentiate those to neurons, muscle cells and cardiomyocytes. Next, we will examine what metabolic changes are induced by the activated ISR in these cells.

In one disease studied by our laboratory, reversible infantile respiratory chain deficiency (RIRCD), the metabolic changes induced by the ISR in the muscle of patients allowed a recovery of the patients from severe disease. Our results indicate that the ISR is protective to some cells and damaging to others. We would like to exploit the knowledge gained in RIRCD to induce similar metabolic changes in mitochondrial conditions that are currently not reversible. Modifying the ISR or manipulating key metabolic factors (amino acids, FGF21) may enable us to devise therapeutic options for mitochondrial translation defects in the future.

References:

1. Hathazi D et al., Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency. Medxiv 2020.
2. Boczonadi V, et al., Horvath R. Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons. Hum Mol Genet. 2018;27(12):2187-2204.
3. 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.
4. Boczonadi V, Jennings MJ, Horvath R. The role of tRNA synthetases in neurological and neuromuscular disorders. FEBS Lett. 2018;592(5):703-717.
5. Richter U, et al. RNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis. Nat Commun. 2018;9(1):3966.
6. Boczonadi V, Ricci G, Horvath R. Mitochondrial DNA transcription and translation: clinical syndromes. Essays Biochem. 2018;62(3):321-340.

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:

1. Boczonadi V, et al., Horvath R. Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons. Hum Mol Genet. 2018;27(12):2187-2204
2. 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.
3. Boczonadi V, Jennings MJ, Horvath R. The role of tRNA synthetases in neurological and neuromuscular disorders. FEBS Lett. 2018;592(5):703-717.
4. Richter U, et al. RNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis. Nat Commun. 2018;9(1):3966.
5. 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.(Bellenguez et al) The association is specific for large artery stroke due to atherosclerosis. (Markus et al)  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.(Brookes et al) 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.

References

1. Bellenguez, C. et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat.Genet. 44, 328–33 (2012).
2. Markus, H. S. et al. Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis. Stroke. 44, 1220–5 (2013).
3. 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) 

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.

References of recent related work from the group

1. Persyn E, Hanscombe KB, Howson JMM, Lewis CM, Traylor M, Markus HS. Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants. Nat Commun. 2020;11(1):2175.
2. Larsson SC, Traylor M, Markus HS. Homocysteine and small vessel stroke: A Mendelian randomization analysis. Ann Neurol. 2019;85(4):495-501.

What Causes 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; Tay et al.  2019), and this has enabled us to develop a novel theory of why apathy occurs in stroke (Tay et al. 2020). In this project, the student will take these studies further to investigate the relationship of 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.

References:

1. 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.
2. Tay J, Tuladhar AM, Hollocks MJ, et al. Apathy is associated with large-scale white matter network disruption in small vessel disease. Neurology. 2019;92(11):e1157-e1167.
3. Tay J, Lisiecka-Ford DM, Hollocks MJ, et al. Network neuroscience of apathy in cerebrovascular disease. Prog Neurobiol. 2020;188:101785.

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 Bellenguez et al). 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 (Brookes et al). 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.

References:

1. Bellenguez, C. et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat.Genet. 44, 328–33 (2012).
2. 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) 

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)

(Co-supervised by Dr Alessandra Granata)

Stroke is often thought as disease of the elderly but a quarter of all strokes occur in individual of working age. Some of these cases are due to single gene disorders (monogenic stroke), and the most common type of monogenic stroke is cerebral small vessel disease (SVD) in which the small blood vessel become diseased resulting in stroke and early onset dementia. 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). 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. 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:

1. Develop an in vitrohuman 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 vitromodel to identify potential new drugable targets for the prevention and cure of stroke.

References:

1. 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).
2. Zellner, A. et al. CADASIL brain vessels show a HTRA1 loss-of-function profile. Acta Neuropathol. 136, 111–125 (2018).
3. 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).

Applying Machine Learning Techniques to Diagnose, and Predict Disease progression, in Vascular Cognitive Impairment. (PhD Only)

(Co-supervised by Professor Zoe Kourtzi, Department of Experimental Psychology)

Cerebral small vessel disease (SVD) causes small deep infarcts (lacunar strokes) and is the major vascular pathology underlying dementia. It becomes common as we age and is a widespread finding on MRI scans. However only a proportion of individuals with these radiological changes progress to dementia. Predicting those who are at risk of progressing is important clinically both for the individual patient, and also to identify a group who should be entered into clinical trials of preventative measures. We have pioneered the use of advanced MRI techniques, particularly diffusion tensor imaging (DTI), to predict dementia risk in SVD.(1,2) However until now we have used relatively simple statistical approaches to analyse the advanced MRI data. Machine learning approaches are increasingly used in prediction in brain diseases. They are well suited to MRI datasets because of the large number of data points that can be obtained.

This project will apply a variety of machine learning approaches to predict dementia risk in patients with SVD. It will build on international collaborations the stroke research group has developed with groups in Netherlands, Germany, Austria and Singapore providing unique prospective MRI datasets. The student will be co-supervised by Professor Zoe Kourtzi in the Department of Experimental Psychology who has particular expertise in applying machine learning approaches to other non-vascular dementias.(2)

The project would particularly suit an individual with mathematical and/or computing expertise.

References

1. Zeestraten EA, Lawrence AJ, Lambert C, et al. Change in multimodal MRI markers predicts dementia risk in cerebral small vessel disease. Neurology. 2017;89:1869-1876.
2. Lawrence AJ, Zeestraten EA, et al. Longitudinal decline in structural networks predicts dementia in cerebral small vessel disease. Neurology. 2018;90:e1898-e1910.
3. Giorgio J, Landau SM, Jagust WJ, Tino P, Kourtzi Z; Alzheimer’s Disease Neuroimaging Initiative. Modelling prognostic trajectories of cognitive decline due to Alzheimer’s disease Neuroimage Clin. 2020;26:102199.

Clonal Haematopoesis and risk of Stroke (PhD Only)

(Co-supervised by Dr Steven Bell)

Clonal haematopoiesis, common in the elderly, arises when a substantial proportion of mature blood cells are derived from a single dominant hematopoietic stem cell lineage. Age-related mutations associated with clonal haematopoietic expansion have been demonstrated to be associated with an increased risk of atherosclerotic cardiovascular disease. It is believed that clonal haematopoesis is one mechanism connecting ageing and inflammation to cardiovascular disease and it has also been offered as an explanation for the occurrence of thrombosis in stroke due to large-vessel occlusion. Recently techniques have been developed which have enabled mosaic chromosomal alterations to be derived from SNP-array data. Investigators have found these are common in the population and correlate with a variety of known risk factors for stroke and other cardiovascular diseases, including diabetes, adiposity and smoking status. It has also been observed that those with detectable mosaicism have an approximately two-fold increased risk for death from all-causes, only partially explained by cancer, leading to speculation that the remaining effect could be via cardiovascular disease. However, further work is required to support this hypothesis, including investigating whether clonal haematopoesis is associated with an elevated risk of stroke (and related magnetic resonance imaging biomarkers), and if so the biological mechanisms linking it to stroke.
This project would be suited to individuals with a science degree background, particularly those with a strong quantitative and/or computing component. A PhD student would gain expertise in applying basic and advanced statistical genetic analysis techniques as well as classic epidemiological analyses.
Key references

1. Jaiswal, S. & Ebert, B. L. Clonal hematopoiesis in human aging and disease. Science 366, eaan4673 (2019).
2. Jaiswal, S. et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N. Engl. J. Med. 377, 111–121 (2017).
3. Sidlow, R. et al. The Clinical Challenge of Clonal Hematopoiesis, a Newly Recognized Cardiovascular Risk Factor. JAMA Cardiol. 5, 958–961 (2020).
4. Loh, P.-R. et al. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Nature 559, 350–355 (2018).

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

Website;  www.pluchinolab.org

Stem Cells of the Ageing MS Brain

(co-supervised with A 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.

Metabolic Control of Brain Stem cell Functions

(co-supervised with C Frezza and A Nicaise)

The proposed project, using techniques such as human stem cell culture, next generation gene editing, and metabolomics, sets out to uncover mechanisms linking inflammatory cues to metabolic reprogramming of human NSCs. This would potentially lead to the discovery of novel molecules and pathways of the NSC-to-immune system communication that could be manipulated to improve NSC activities in therapeutic settings. Additionally, since NSCs have the potential to be used as a therapy in disease, their metabolic profile under inflammatory conditions is important to understand.

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

(co-supervised with J Marioni and R Hamel)

Secondary injury mechanisms in traumatic spinal cord injury are exacerbated by morphological, molecular, and functional changes in immune cells, such as CNS-resident microglia and CNS-infiltrating monocyte derived cells, which have yet to be fully characterized. Consequently, therapeutic approaches aiming at the modulation of immune cell reactivity remain controversial. The goal of this project is to investigate the molecular mechanisms of immune cell reactivity and the long-lasting epigenetic changes in these cells upon SCI. To this end, we will employ the novel combined technology of ex vivo single-cell RNA and ATAC sequencing to obtain high-throughput gene expression and chromatin accessibility profiling.

These results are expected to ultimately lead to a better understanding of the secondary injury and 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 immune profiles in the future.

Metabolic Determinants of Persistent Brain Inflammation

(co-supervised with L 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.

The Role of Mitochondria in Neuroinflammation

(co-supervised with L 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.

SUCNR1/GPR91 Signalling in Astrocyte – Microglial Interactions

(co-supervised with C Willis)

Metabolites are intermediates of cellular metabolism that regulate energy homeostasis through anabolic and catabolic reactions. However, recent evidence uncovered exciting new roles for metabolites, which act as intracellular and extracellular signalling molecules in health and disease. In chronic inflammation, succinate, an intermediate of the tricarboxylic acid cycle, plays a key role in modulating inflammatory innate immune responses via autocrine and paracrine signals through its cognate G-protein coupled receptor 91 (gpr91).

The goal of this project is to address the role of succinate/gpr91 signalling in regulating the inflammatory role of astrocytes, the most abundant glial cell in the central nervous system.

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

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

I founded a new ultra-high field (7T) MRI physics group in Cambridge in 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 methods for parallel transmit neuroimaging. We have performed some of the first parallel transmit work on the new 7T Terra platform. We wish to extend this to optimise whole brain diffusion and magnetisation-transfer imaging. This will involve both method-development and translation to scanning in relevant patient groups. This project would be in close collaboration with Siemens Healthcare’s UK and HQ development team.
(ii) Developing methods for imaging glycolytic metabolism in humans 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 in the body and in the brain. I am particularly interested in developing DMI as a means to probe the heart’s substrate selectivity for fats vs sugars which plays a key role in the mechanism of heart failure.
(iii) Developing methods for multinuclear imaging in the brain or body. For example, using a new whole-body 31P and 1H coil built for us by Tesla Dynamic Contrast to probe heart and liver oxidative metabolism in collaboration with collegues at Royal Papworth hospital. Or in a planned multi-site collaborative study of neuro-metabolism and its changes in disease.
(iv) Developing methods for motion-corrected functional imaging or cortical layers or deep brain nuclei; or for imaging blood flow in small vessel disease.

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 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) – Anesthesia

 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.

The default mode network in consciousness (PhD/MPhil)

Brain injury management has improved considerably in recent years with resulting significant improvements in outcome. Nevertheless, a small but significant number of survivors do not fully emerge after acute coma and remain in prolonged disorders of consciousness (DoC), including vegetative and minimally conscious states. Long range brain networks, such as the default mode network (DMN), have been shown to be disrupted in DoC, and are partially or fully restored when patients recover cognitive capacity. The functional role of the DMN remains unclear. Although it was initially considered to be a task negative network, recent studies from our group and others have revealed DMN activity/connectivity during a wide range of self-referential and memory-based tasks, as well as altered DMN integrity in a variety of neuropsychiatric disorders. Such data provide support for inferences on the role of the DMN in cognitive capacity and consciousness. An emerging theory is that the DMN acts as a global workspace integrating information from a variety of sources through associations, to make sense of the world at present. The major hubs of the DMN are multisynaptic and are connected to both cortical and subcortical regions rendering this network a suitable candidate for integrating information. Within this emerging theoretical framework this project will utilise fMRI/EEG to focus on the role of the DMN at rest but also importantly during tasks, in a cohort of DoC patients and healthy volunteers. Experience in neuroimaging and/or electrophysiology is required for this project. Skills in scientific computing and programming (e.g, Linux, Matlab, Python) are desirable.

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 or MPhil, PhD preferable)

Mitochondrial diseases are caused by defects in genes required for energy production and oxidative phosphorylation (OxPhos). We find it intriguing that some patients with mitochondrial disease present late in life, with very tissue-specific phenotypes. It seems that not all cells and tissues are equally susceptible to mitochondrial disease.

The objective of this project is to study how specific cells respond to mitochondrial dysfunction within the context of a living organism. We plan to find out whether interactions between different cell types, may render cells and tissues more, or less, vulnerable to mitochondrial disease. The project will focus on the developing Drosophila brain and aims to investigate how neural stem cells interact with their surrounding glial cells in the 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.

Safeguarding the Nuclear Genome in Mitochondrial Disease (PhD or MPhil, PhD preferable)

There is a constant interaction between mitochondria and the nucleus, with changes in each compartment affecting homeostasis in the other. DNA replication, histone modification and transcription all have specific metabolic requirements, and these may provide a direct link between gene expression and the metabolic status of the cell, tissue or organism.

The objective of this project is to uncover novel mechanisms that protect the nuclear genome from changes in metabolism due to mitochondrial dysfunction. Taking advantage of genetically encoded metabolite sensors, we will study nucleus/cytoplasm metabolite ratios in vivo in the Drosophila brain and in cell culture, and determine how these are affected by acute and chronic mitochondrial dysfunction. We next aim to identify novel regulators of nuclear metabolism and profile their cell-type specific genome-wide impact on transcription and histone modifications in vivo in NSCs and glia. The project will rely mostly on confocal imaging, CRISPR/Cas9-mediated genome editing and cell-type specific DamID-seq. We hope to provide insight into communication between mitochondria and the nucleus, and find mechanisms that buffer transcriptional output when confronted with cell- or tissue-wide changes in mitochondrial activity.

References

1. van den Ameele J, Li AYZ, Ma H, Chinnery PF. Mitochondrial heteroplasmy beyond the oocyte bottleneck. Semin Cell Dev Biol. 2020 Jan. 97:156-66.

2. van den Ameele J, Brand AH. Neural stem cell temporal patterning and brain tumour growth rely on oxidative phosphorylation. eLife. 2019;8:e47887.

3. van den Ameele J, Krautz R, Brand AH. TaDa! Analyzing cell-type specific chromatin in vivo with Targeted DamID. Curr Opin Neurobiol. 2019. 56:160–166.

4. Aloia L, et al. Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration. Nat Cell Biol. 2019 Nov;21(11):1321-33.

5. Cheetham SW, et al. Targeted DamID reveals differential binding of mammalian pluripotency factors. Development. 2018 Oct 17;145(20).

Dr Debi Vickers (dav1000@cam.ac.uk) 

Understanding how People using Cochlear Implants Process Sound for Speech Perception

Cochlear implants have been proven to be one of the most effective interventions for restoring hearing for the people who suffer from severe-to-profound deafness. This cochlear implant works by converting acoustic sound information to electrical pulses which are sent to the intra-cochlear electrodes, that then directly stimulate the hearing nerve which starts the process of transmission of sound through the auditory pathways to the cortex.

There are three projects to help us to gain a better understanding of how sound is processed by cochlear implant listeners;

1)     How are Bilateral Cochlear Implant users affected by Mismatched Information Presented to the Different Ears?

(Co-supervisor: Dr Ben Williges)

This project will involve testing normal hearing listeners with simulations of cochlear implant sound processing.  Adjustments will be made to the simulations to help understand the relationship between how different sounds are processed at the two ears and the impact it has on speech perception.  Factors than will be adjusted are: the fidelity of the frequency information conveyed (essentially explores the effects of traumatic electrode insertion and neural degeneration of the hearing nerve) and mismatched frequency information ( simulates different insertion depths of the electrodes in each ear).

All of the testing will be conducted in a virtual acoustic environment to simulate hearing in an everyday situations.   Test materials will be presented over headphones.

2)     Do the Differences in Depth of Insertion of Electrode Arrays affect the Speech and Language Outcomes for Children with Bilateral Cochlear Implants?

(Co-supervisor: Dr Ben Williges and Prof Manohar Bance)

This project will be an audit of patient notes to determine if the depth of insertion of electrodes measured using the post-operative x-rays affects the rate at which children acquire speech and language.  In particular, this project will focus on the difference in the depth of electrode insertion in each ear.  The student taking this project will work through online information and will need a research passport to be able to access the relevant data for the project.  Individual factors will need to be accounted in the statistical analysis, such as age at implantation, home language and aetiology.

3)     Understanding the Relationship between Ability to Discriminate Speech-Like Sounds and the Relationship to Speech Understanding for Cochlear Implant Users.

(Co-supervisor: Dr Wiebke Lamping)

Cochlear implant users are especially reliant upon temporal (timing) information to be able to understand speech.  Different speech sounds have different temporal information and the ability of the cochlear implant user to hear the differences between these different cues affects how well they can use speech information.  This ability can be further affected when individual electrode contacts don’t deliver appropriate information due neural dead regions or issues with electrode placement.  The goal is to develop a test that can help to identify these poor electrode contacts but also to better understand the relationship between the perception of these temporal cues and speech perception.  We have already conducted various pilot studies to help us refine the protocol and develop the measures for this study.

There are two options for this project.  The first is to run simulations of cochlear implant processing and simulated neural dead regions.  The second is to work directly with adults using cochlear implants.  We can discuss the most appropriate approach to take.

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.

Dr Patrick Yu-Wai-Man (py237@cam.ac.uk) – Neuro-Ophthalmology and Genetics (PhD only)

I am an academic neuro-ophthalmologist with a major research interest in mitochondrial genetics and inherited eye diseases. My research group is focused on new gene discovery and we are using a multipronged approach to dissect the disease pathways contributing to progressive neuronal loss and blindness, including zebrafish models and patient-derived induced pluripotent stem cells.

I coordinate a specialist clinical service for patients with mitochondrial eye diseases in Cambridge and London. Over the past 20 years, we have established a national cohort of patients with inherited optic neuropathies, and we are using this unique resource for deep phenotyping, biomarker profiling and to push forward with an active translational research programme, including gene therapy.

I have long-standing collaborations with other principal investigators in the Cambridge Centre for Brain Repair, the Cambridge MRC Mitochondrial Biology Unit and the UCL Institute of Ophthalmology in London. This extensive research network will provide the student with access to a wide source of expertise, tailored supervision and the opportunity to develop a broad skill set as the project evolves.

Project Themes:

• Elucidating the missing heritability in inherited optic neuropathies
• Dissecting disease mechanisms using iPSC-derived retinal ganglion cells
• Zebrafish models of Wolfram syndrome and therapeutics
• Gene therapy for inherited optic neuropathies

Publications:

https://pubmed.ncbi.nlm.nih.gov/?term=YU-WAI-MAN+P&sort=pubdate