Role of median eminence myelin plasticity in the regulation of energy homeostasis
Supervisor: Dr Clemence Blouet, PI (csb69@medschl.cam.ac.uk)
Principle Supervisor Department: Clinical Biochemistry
Summary
Recent work from our team characterised the unique plasticity of oligodendrocyte lineage (OL) cells of the median eminence, a region of the hypothalamus that is critical for the regulation of energy and glucose homeostasis. We found that OL progenitors rapidly proliferate and differentiate into myelinating oligodendrocytes in adult healthy mice, and local myelin continuously turns over. Intriguingly, such plasticity is unique to this brain regions, raising questions regarding its functional relevance. Acute and long-term nutritional challenges significantly modify median eminence OL plasticity and myelin turnover. In particular, obesity is associated with an impressive accumulation of myelin, ectopic myelin formation and altered myelin lipid composition, but the functional consequences of these changes are unknown.
In this project, we propose to characterise the role of median eminence hypermyelination in obesity in the control of energy and glucose homeostasis. We will use transgenic mouse models to either delete Myelin Basic Protein from adult-formed oligodendrocytes, leading to hypomyelination in the median eminence, or block oligodendrocyte turnover by deleting TFEB in oligodendrocytes, a model of hypermyelination. We will characterise molecular and structural changes occurring in median eminence myelin in obesity using genetic fate mapping of myelin, transcriptomics and lipidomics. We will determine whether human obesity also produces hypermyelination and decreases oligodendrocyte plasticity in the human median eminence. Lastly, we will characterise the functional consequences of median eminence hypermyelination on hypothalamic neuroendocrine and nutrient sensing functions.
This research will significantly increase our understanding of the role of median eminence myelin in metabolic health and metabolic diseases, and will likely generate new mechanistic knowledge that might translate into the identification of new drug targets to improve metabolic health in obesity.
The use of blood biomarkers for the early and differential diagnosis of dementia
Supervisor: Dr Leonidas Chouliaras, Assistant Professor (lc716@medschl.cam.ac.uk)
Principle Supervisor Department: Psychiatry
Summary
This project will focus on the use of blood plasma biomarkers of neurodegeneration and their role in the early and differential diagnosis of dementia. Blood biomarkers of neurodegeneration such as Phospho-tau (ptau)-181 and 217, glial fibrillary acidic protein (GFAP), amyloid beta (Αβ) 42/40 and neurofilament light (ΝfL) have shown high performance for the early diagnosis of Alzheimer’s disease (AD) pathology. However, their use for the diagnosis of non-AD dementias requires further development and likely additional research. Our group has previously shown that Ptau181 and GFAP plasma markers show excellent potential in differentiating AD from controls, frontotemporal lobe degeneration as well as progressive supranuclear palsy but do not perform as well in differentiating AD from Lewy Body Dementia (LBD). Furthermore these markers are not able to detect AD co-pathology in LBD.
This project aims to build up on ongoing work and test the accuracy and performance of blood biomarkers of neurodegeneration for the differential diagnosis of dementia. Building up to previous work will test novel biomarkers , such as ptau-217 and ptau-231 as well as markers of brain derived tau and synaptic function in cohorts from the Cambridge Centre for Parkinson’ plus disorders. It also aims to test whether such biomarkers can be used to detect AD co-pathology in LBD. It will also aim to test the associations between plasma biomarkers and brain imaging such as PET markers of synaptic function and neuroinflammation in AD and LBD using various statistical models including mixed linear models, area under the curve statistics and more advanced methods such as machine learning. The project will also test multimodal models and test whether addition of genetic information can improve the diagnostic accuracy of biomarkers.
This project will ideally suit a clinically qualified candidate as their role will involve assessment and recruitment of research participants, collaborative work on the processing and analysis of plasma biomarkers, brain imaging data analysis and interpretation and publication of findings.
Research questions:
1. Which plasma biomarkers perform best for the differentiation of AD from LBD?
2. Which plasma biomarker can best predict longitudinal decline and could potentially be used as a marker of disease progression and disease modifying treatment?
3. Are plasma biomarkers associated with neuroimaging endophenotypes?
4. Can the performance of plasma markers be improved by the addition of genetic, epigenetic and proteomic information for multivariate risk prediction models?
Utilising eye tracking as a novel measure of remyelination and neuroprotection in people living with multiple sclerosis
Supervisor: Dr Nicholas Cunniffe, Clinical Lecturer in Neurology (ngc26@cam.ac.uk)
Principle Supervisor Department: Clinical Neurosciences
Summary
The most urgent need for the 125,000 people in the UK living with multiple sclerosis (MS) are treatments which prevent disability progression. Regenerating the myelin lining of nerves (remyelination), which prevents cell death, is the best way to achieve this. However, the optimum method to test remyelination in people is unknown.
This project tests the hypothesis that improvements in eye movements, which are commonly affected by MS, can serve as a sensitive marker of remyelination. Reaction times, or saccadic latencies, are known to be abnormal in MS and might improve with neuroprotection. An alternative is to interrogate remyelination of the medial longitudinal fasciculus (MLF), which results in an eye movement disorder termed internuclear ophthalmoplegia (INO).
The candidate will examine these in people with MS using a video oculometer, both in an observational study, and in the setting of a phase 2 remyelination trial. They will compare eye movement data to the current standard measures (magnetization transfer ratio of lesions and visual evoked potential latency). Their conclusions will be highly impactful for future remyelination trial design.
This is a clinical research project. Candidates should have a strong background in translational medicine and must have excellent interpersonal skills.
The role of type I interferon in Alzheimer’s disease
Supervisor: Dr William McEwan, Principal Research Associate (wm305@cam.ac.uk)
Principle Supervisor Department: Clinical Neurosciences
Summary
The Alzheimer’s diseased brain is an inflamed state. One of the main characteristics of this inflammation is the production of type I interferon (IFN-I), more normally associated with viral infections. Our recent work has implicated this response as a critical element in driving tau aggregation (Sanford et al 2023). The current project will therefore examine whether there is a more general role in linking the IFN-I the AD brain with tau pathology.
The project will involve wet lab experiments in cultured cells, analysis of mouse tissue using IHC and analysis of transcriptomic data. Experience with one or more of these techniques is therefore desirable.
CRISPR screens for anti-obesity drug discovery
Supervisor: Dr Florian Merkle, Sir Henry Dale Fellow (fm436@medschl.cam.ac.uk)
Principle Supervisor Department: Clinical Biochemistry
Summary
Studies of individuals with rare monogenic forms of obesity, and large-scale genome-wide and exome-wide genetic association studies (GWAS and ExWAS) are revealing an ever-increasing number of obesity-associated genetic variants.
We hypothesise that interrogating the genetics of obesity at scale across obesity-relevant cell types will accelerate mechanistic discovery and prioritise targets for future therapeutic development. We will therefore use pooled CRISPR screens to knock down candidate genes or introduce specific single nucleotide variants (SNVs) in parallel into KOLF2.1J human pluripotent stem cells, and differentiate edited cells into appetite-regulatory hypothalamic neurons, including pro-opiomelanocortin (POMC) neurons.
We have previously demonstrated that these cells resemble their counterparts in the human brain, respond to the existing anti-obesity drug Semaglutide (Ozempic/Wegovy) and can be used to identify new candidate drugs (see doi 10.1101/2023.07.18.549357). Specifically, we will prioritise hits that preferentially affect hypothalamic neurons, are druggable, and/or act in obesity-associated pathways when perturbed. We will then test the localisation of candidate genes in the human brain to gain insight into relevant cell populations using spatial transcriptomics and RNAscope, and test the effect of gene knockdown on mouse body weight.
How does the cerebral cortex sense and adapt to nutritional state?
Supervisor: Dr Zahid Padamsey, Senior Research Associate/MRC Career Development Fellow (zp278@cam.ac.uk)
Principle Supervisor Department: Clinical Biochemistry
Summary
The brain is energetically expensive. Despite comprising 2% of our body’s mass, it consumes 20% of our caloric intake. Whilst it has been widely assumed that brain energy use is invariant to changes in caloric intake, recent work by our lab has suggested otherwise (Padamsey et al., 2022; Neuron; DOI: 10.1016/j.conb.2022.102668; see coverage in Wired Magazine: https://www.wired.com/story/the-brain-has-a-low-power-mode-that-blunts-our-senses). Indeed, we find that, contrary to expectations, calorie restriction in mice reduces brain energy use, impairing brain function; the brain essentially enters a “low power mode” to save energy. Mechanistically, the link between caloric intake and brain function is poorly explored, though is likely mediated by circulating metabolic hormones, like leptin, which convey nutritional status to the brain. Critically, neurons across the brain also express receptors for these hormones, and are therefore capable of directly sensing peripheral nutritional state.
The proposed project will examine how metabolic hormones, and their receptors, affect neuronal energy use and function in the cerebral cortex – the most energetically expensive brain region. The project will use state-of-the-art calcium, ATP, and oxygen imaging, as well as whole-cell patch clamp electrophysiology to record neuronal function and energy use in vitro (primary neuronal culture and cortical slices) and in vivo (in awake, head-fixed mice), combined with pharmacological and genetic manipulations of metabolic signalling pathways. The findings of this project will be critical for generating novel drug targets for improving brain energy use and function.
Metabolic control of microglia regulating neuronal functions
Supervisor: Dr Luca Peruzzotti-Jametti, Senior Research Associate (lp429@cam.ac.uk)
Principle Supervisor Department: Clinical Neurosciences
Summary
Chronic, low grade, inflammation plays a critical role in inflammatory and degenerative central nervous system (CNS) disorders characterised by an irreversible decline of cognitive functions. Currently, there is no therapy that can meaningfully interfere with this pathobiological process, mostly due to an incomplete understanding of the mechanisms regulating immune responses and related neuronal vulnerability.
This project will test the hypothesis that microglia, the CNS resident immune cells, drive persistent CNS inflammation by acquiring metabolic states that cause selective neurotoxicity and associated cognitive deficits.
To challenge this hypothesis, we will study the role of microglial metabolism in modulating the function of neuronal networks in complementary mouse models of CNS inflammation (Work Package 1). We will then interfere with specific metabolic pathways that we found to be dysregulated in microglia during inflammation (i.e., succinate and lipid metabolism) to study the interactions between microglia and neural cells in vitro and stop inflammatory-induced cognitive decline in vivo (Work Package 2).
Investigating how cell metabolism influences microglial activation states and their effect on CNS structure and function offers concrete chances to (i) advance our understanding of neuro-immune interactions and (ii) develop new therapeutic approaches that will preserve cognitive functions in CNS disorders and across lifespan.
Disease pacemaker Stem Cells in Neurodegenerative Disease
Supervisor: Professor Stefano Pluchino, Professor of Regenerative Neuroimmunology and Honorary Consultant Neurologist (spp24@cam.ac.uk)
Principle Supervisor Department: Clinical Neurosciences
Summary
The presence and role of neural stem cells (NSCs) in the adult human brain is a long-debated issue in neuroscience. Recent work has demonstrated that stem-like cells exist in the embryonic, foetal, and human adult brain where they persist well into adulthood and can even contribute to neurogenesis.
However, their role in neurodegenerative disease is unknown. Ongoing work in the lab has led to the hypothesis that NSCs may become dysfunctional in neurodegenerative disease resulting in senescence chronic inflammation, and thereby acting as pacemaker cells driving neuronal demise.
This ambitious project aims to identify disease-associated NSCs and their phenotype in the context of human neurodegeneration using spatial biology approaches, including imaging mass cytometry, RNA scope and single nuclear RNA sequencing.
Relying on post-mortem brain tissue of different stages of Alzheimer’s disease, traumatic brain injury, vascular dementia and chronic stroke, this project will study NSCs in a range of human diseases characterised by neurodegeneration and neuronal injury.
Ongoing work in the lab identifies NSC-specific markers based on transcriptomics and protein profiling experiments in brains with progressive multiple sclerosis, enabling to investigate the distribution of NSCs in a wide range of diseases. Spatial transcriptomics and proteomic approaches will allow to study their phenotype and dysfunction in relation to other cell types and local pathology. This project will shed light on the role of NSCs in neurodegeneration and has the potential to identify an entirely novel mechanism of neurodegeneration in human disease.
Understanding neurodegenerative tauopathies with multimodal neuroimaging and neuropathology data
Supervisor: Dr Timothy Rittman, Senior Clinical Research Associate (tr332@medschl.cam.ac.uk)
Principle Supervisor Department: Clinical Neurosciences
Summary
This project will address the systems level progression of neurodegenerative tauopathies. By integrating neuroimaging and neuropathology data from a large cohort of people with neurodegenerative tauopathies, this project will utilise machine learning approaches to integrate these data into a single model of disease. This model will be used to understand the progression of neurodegenerative tauopathies in terms of neuronal loss, synapse loss, inflammation, and protein aggregation. Each of these mechanisms will be measured using neuroimaging modalities (PET, MRI) and post-mortem neuropathology data. These models will be used to identify single or combined disease targets, and to evaluate the potential impact of disease modifying treatments.
An understanding of neuroimaging is desirable, with a willingness to learn about neuropathology and statistical/machine learning models. The lab group has links to the computer science and maths departments to support model development, and a large existing dataset on which to work. The lab encourages an open science approach and an inquisitive nature.
Ultra-high field (7T) MRI development
Supervisor: Professor Chris Rodgers, Professor of Biomedical Imaging (ctr28@cam.ac.uk)
Principle Supervisor Department: Clinical Neurosciences
SummaryI lead Cambridge’s 7T MRI physics group. We create new types of MRI scan to study the human brain and body. We collaborate with world leading clinicians in neuroscience, epilepsy and cardiology (Papworth).
We have openings for a PhD on:
(i) Human 7T 2H deuterium metabolic imaging (DMI). This is a promising new technique that may compete with 18FDG-PET, but without radiation. We are now running a study using glucose DMI to probe glycolytic metabolism changes in early-stage Alzheimer’s disease. We are starting a study using fumarate DMI to probe the response to therapy in patients with brain tumours. We have excellent equipment and approvals secured for these studies. This is a great opportunity to bring a new imaging modality into use in patients.
(ii) Developing new pulse sequences for neuroimaging using parallel transmit technology. Parallel transmit uses multiple RF transmitters together with special pulse design algorithms to make 7T images that cover the whole brain uniformly and that cause minimal heating of the subject. We have recently patented two parallel transmit approaches, and we are continuing to build our momentum in this area in collaboration with Siemens. We are running a world leading clinical study applying parallel transmit 7T MRI to find the tiny lesions that cause epilepsy in patients where conventional hospital 3T MRI and PET imaging has failed to help them. This could transform their lives by giving them access to surgery, which has an 80% success rate to stop seizures but only if the location of the lesion is known.
We look for students with strong maths skills and ideally programming experience in C/C++, python or Matlab (or a willingness to learn). 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.
Understanding pathways which can reduce alpha-synuclein accumulation in Parkinson’s disease and Dementia with Lewy Bodies
Supervisor: Professor David Rubinsztein, Professor of Molecular Neurogenetics (dcr1000@cam.ac.uk)
Principle Supervisor Department: Cambridge Institute for Medical Research (CIMR)
Summary
Parkinson’s disease and Dementia with Lewy bodies manifest with accumulation of alpha-synuclein in Lewy bodies, particularly in the brain regions involved in memory and motor control. Currently, there are no treatments that can slow or stop the brain cell damage in these diseases. Extensive data, including the existence of Parkinson’s disease cases caused by extra copies of the alpha-synuclein gene, argue that alpha-synuclein accumulation is sufficient to cause such diseases. Thus, reducing the levels of alpha-synuclein is a reasonable strategy for Parkinson’s disease and Dementia with Lewy bodies.
David Rubinsztein’s lab showed that alpha-synuclein is cleared by two processes in the cells – autophagy and proteosomal degradation. They have shown that enhancing autophagy can reduce alpha-synuclein deposition and ameliorate neurodegeneration in cells and mice. However, there is a poor understanding of the specific proteins and pathways which control autophagy and proteosomal clearance to prevent alpha-synuclein accumulation. To address this, they have conducted and completed an unbiased genome-wide screen to identify targets or genes whose absence increases or decreases alpha-synuclein levels in cell culture. This project will focus on validation of selected hits and defining new mechanisms regulating alpha-synuclein turnover, with the view to identifying therapeutic targets.
The project will be primarily focussed around cell culture studies in different cell systems, including induced pluripotent cell-derived neurons, where the lab have established systems enabling accurate quantification of alpha-synuclein levels. Within the timeline of the project there will be the potential to study hits in novel zebrafish models of alpha-synuclein pathology that the lab has established and published.
Achieving onco-functional balance in the treatment of paediatric brain tumours
Supervisor: Dr John Suckling, Director of Research in Psychiatric Neuroimaging (js369@cam.ac.uk)
Principle Supervisor Department: Psychiatry
Summary
Primary brain tumours are the most common form of solid malignancy in childhood. Surgical resection with adjuvant chemo- and radio-therapy is the most common treatment and more patients are surviving to adulthood. But increasing surgical margins to improve survival can also induce cognitive deficits, and a balance between survival and quality of life is a priority in therapeutic decision-making.
Our prior research with adults with brain tumours has shown that even non-aggressive tumours can induce cognitive changes due to disruption of functional networks at large-scales across the cortex. Common adult brain tumours – gliomas – preferentially grow in high metabolic regions that act as bridges between functional networks that sub-serve key cognitive functions, and that tumours affecting these bridges have the greatest impact on cognition. Alterations to functional networks by tumours are also produced by neurite (axons and dendrites) disruption extending beyond the tumour margin. Surgical plans for tumour resection also significantly impact cognition.
Whilst adult brain tumours are heterogeneous in their genes, histology and morphology, their effects on cognition and functional networks are remarkably consistent. Childhood brain tumours have even greater variability in their presentation, origins, and aetiology. This project seeks to understand whether effects of childhood tumours on surrounding unaffected tissue conform to the principles discovered for adult tumours or are uniquely different; and to develop models to predict the cognitive and educational outcomes from longitudinal brain imaging acquisitions together with other relevant demographic, cognitive and clinical variables.
This study is following children aged 8-15 with brain tumours through their treatment with assessments pre- and post-operatively and twice more during the subsequent recovery period. It is hosted in the Brainbow neuro-oncological rehabilitation service at Addenbrookes’ hospital.
IMAGE-D: Integrated Multimodal Analysis for Gaining Enhanced Understanding and Characterization of Dementia
Supervisor: Dr Kamen Tsvetanov, Senior Research Associate (kat35@cam.ac.uk)
Principle Supervisor Department: Clinical Neurosciences
Summary
Dementia encompasses various subtypes such as Alzheimer’s disease, vascular dementia, and frontotemporal dementia, each affecting different aspect of brain structure and function. While various imaging techniques like structural MRI, functional MRI, PET scans, and DTI exist to capture these differences, their limited combined use hampers a thorough understanding of dementia subtypes, potentially missing valuable insights into underlying brain changes and individual variations.
By leveraging a multimodal approach in interdisciplinary setting and utilizing existing imaging datasets, such as cohorts linked to Dementia Platform UK, the project seeks to distinguish between different dementia types, track disease progression, and enhance our knowledge of their unique characteristics.
The developed methodology will also allow for the integration of imaging data with other biological or clinical information, such as genetics, biochemical markers, or neuropsychological assessments, enabling exploration of the relationships between brain changes, molecular pathology, and clinical symptoms.
This project offers an exceptional opportunity to advance knowledge in the field, develop expertise in multimodal neuroimaging, cutting-edge data science and advanced data analytics, aimed at understanding the intricate mechanisms underlying neurodegenerative diseases. Engaging in this project offers the chance to make not only significant contributions to dementia research, but also to refine interdisciplinary skills at the intersection of data science and neuroscience.
Relevant references:
Liu et al (2022). Human Brain Mapping, https://doi.org/10.1002/HBM.26025
Liu et al (2023). Neurobiology of Aging, https://doi.org/10.1016/J.NEUROBIOLAGING.2023.06.001
Passamonti et al (2019). The Journal of Neuroscience, https://doi.org/10.1523/jneurosci.2574-18.2019
Tsvetanov et al (2020). Alzheimer’s & Dementia, https://doi.org/10.1002/alz.12209
Methods for quantitative MRI
Supervisor: Professor Guy Williams, Professor of Imaging Science (gbw1000@cam.ac.uk)
Principle Supervisor Department: Clinical Neurosciences
Summary
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.
Mapping the feeding circuitry in the human brain using single cell and spatial transcriptomic approaches.
Supervisor: Professor Giles Yeo, Professor of Molecular Neuroendocrinology (gshy2@cam.ac.uk)
Principle Supervisor Department: Institute of Metabolic Science
Summary
The prevalence of obesity has increased dramatically over the past three decades. While changing lifestyle and environment have undoubtedly driven this increase, there is a powerful genetic component that underlies the large variation in human body-weight. Genetic studies point to the brain, particularly the hypothalamus, as having a crucial role in modulating appetite, limiting, until now, the mechanistic insights achievable through human research.
Using single-nuclear RNA sequencing (NucSeq) and spatial transcriptomics approaches, we are determining how the hypothalamic architecture underlying appetitive control differs in the underweight and overweight human brain. We will study brains from donors at both extremes of body-weight from the MRC Brain Bank Network, and also from donors diagnosed with Prader Willi Syndrome. A study of human hypothalami from donors across the weight spectrum is crucial both for understanding the physiology of the control of appetite, and in enabling us to improve the health of the population in the modern food environment.