Research Opportunities

Evolution has produced an arms race between viruses and the cells they infect. Studying this battle provides key insights into cell biology and immunology, as well as the viruses themselves. It may even lead to the development of novel therapeutics. The Matheson lab therefore focuses on two pandemic viruses with a major impact on human health: HIV and SARS-CoV-2.  

We have previously used unbiased proteomics to quantify dysregulation of hundreds of proteins and processes in infected cells, and now aim to understand the importance of these targets for both viral pathogenesis and normal cellular physiology. Because HIV regulates numerous cell surface amino acid transporters, we are particularly interested in amino acid metabolism and protein biosynthesis.  

Depending on the interests of the student, this project will therefore focus on either (1) an orphan cell surface amino transporter downregulated by SARS-CoV-2 infection of respiratory epithelial cells or (2) an ancient metabolic enzyme regulating ribosomal frame shifting depleted by HIV infection of primary human CD4+ T cells.  

In either case, the aims will be to: validate the target in different systems; define the mechanism of viral regulation; determine the functional effects of target depletion in biochemical and cell biological assays; and characterise the impact of target depletion on viral infection. Opportunities will be available to conduct further proteomic screens, perform ribosomal profiling and/or stable isotope-based metabolomics.   

The project will provide training in a wide range of molecular and biochemical techniques, whilst allowing the student to explore an important aspect of the host-virus interaction. The Matheson lab is based in the brand new Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), including the largest academic Containment Level 3 (CL3) facility in the UK. The student will be supervised by an experienced postdoc in a friendly, supportive group. 
 

The brain is continuously bombarded with visual input but has limited processing capacity. Learning to selectively process visual features relevant for behaviour is therefore crucial for optimal decision-making and thought to rely on activity of GABAergic inhibitory interneurons. Altered inhibition is linked to perceptual and learning impairments and associated with neurodevelopmental disorders including schizophrenia and autism.

The aim of this project is to understand the precise role of different types of GABAergic inhibitory interneurons during visually-guided learning and decision-making. Mice have a similarly organized visual cortex and show complex decision-making behaviours. Mouse brain circuits can be measured and manipulated during behaviour in ways not possible in humans.

Our approach is to train mice, including pharmacological and genetic mouse models of neurodevelopmental disorders and healthy controls, in visual decision-making tasks. We measure activity in visual cortex in specific cell types using 2-photon imaging and electrophysiology and use optogenetics to activate or inactivate activity of specific interneuron cell types. We will also apply two new innovative methods to optically measure the inhibitory neurotransmitter GABA (developed in the Looger lab, UCSD) and to locally pharmacologically manipulate GABA levels in the brain (collaboration with Malliaras and Proctor labs, Dept of Engineering, Cambridge) during visual learning and decision-making.

The PhD project is associated with a Wellcome Trust funded Collaborative programme with a cross-disciplinary international research team to investigate the role of GABAergic inhibition in both mice and humans at different scales, from local circuits to global brain networks.

Lab website: https://www.pdn.cam.ac.uk/svl
Contact: Jasper Poort jp816@cam.ac.uk

There has been increasing interest in applying computational methods in medicine, to make sense of cancer’s ‘big data’ problem by exploiting recent advances in data-processing and machine learning to capture and integrate clinical, genomic, and image data collated from hundreds of cancer patients in real-time. Such methods can be applied to digital clinical images to extract image information about patterns of pixels that are not perceivable to the human eye, allowing characterisation of tumour.  Prostate cancer is the 2nd commonest male cancer worldwide, and MRI is the diagnostic tool of choice, however, MRI can miss 10% of significant tumours and leads to unnecessary (invasive) biopsy in around 1/3rd patients who do not have cancer.  

We will use a prototype AI system (Pi) developed with Lucida Medical on retrospective data, in a prospective clinical study. We plan to link histological data to imaging features derived from MRI (including texture analysis) to identify predictors of lesion aggressiveness and need for sampling, using biopsy cores and surgical specimens from the prospective cohort. Further work will link biopsy tissue to MRI data to identify radiogenomic markers of disease aggressiveness. The project presents an opportunity for AI to answer key clinical questions at the intersection of interpretation, imaging and biopsy.  

The project will involve working with an established interdisciplinary programme of researchers and help in the assessment of cross-cutting “multi-omic” approaches to cancer assessment, involving integration of advanced image analysis, transcriptomic, genomic, tissue, and patient outcomes to inform the design of diagnostic strategies.

We are developing artificial multi-valent proteins capable of liquid-liquid phase separation (LLPS) with the aim of building multi-functional biomolecular condensates and thereby harnessing specific cellular enzymes to target disease-associated proteins for destruction. We propose to design condensates that contain a class of proteins known as tandem-repeat proteins (RPs). We have shown that RPs are strikingly amenable to rational design and can be engineered to simultaneously bind multiple proteins, bringing them into specific spatial proximity in such a way as to enable a chemical modification of the target protein. The rational design of LLPS systems capable of selectively recruiting client proteins into them to drive specific biological reactions would enable both a deeper understanding of the role of biomolecular condensates in nature as well as the exploitation of their remarkable physico-chemical properties for therapeutic effect. 

Key areas of interest include: 
 

1. Understanding the molecular grammar of protein phase separation to define rules for creating designer LLPS systems. 

2. Developing novel hetero-bifunctional phase-separating proteins to recruit disease-associated targets to the protein degradation machinery. 

3. Translating the designed LLPS proteins into biomolecular condensates in the cell capable of enhancing targeted protein degradation. 

“Life will find a way….” In a now famous quote from the 1993 movie Jurassic Park, the “chaotician” Ian Malcolm nicely captures the essence of adaptation through evolution. But series evolutionary change often requires multiple mutations to arise – the changes arising from SNPs and indels in single genes usually amount to little more than phenotypic “tinkering”. So what would happen if we could “step on the evolutionary gas pedal” and accelerate the pace of change? Or alternatively, what would be the consequences of “slamming on the evolutionary brakes” to prevent adaptation? Well, these are just the kind of approaches that we have developed in the Welch lab, and we are applying these to look at how the opportunistic bacterial pathogen, Pseudomonas aeruginosa, adapts to the presence of infection-relevant selection pressures. Essentially, we’ve engineered the mismatch-repair system to come under the control of an inert chemical inducer, and so can “rheostatically” modulate the rate of mutation from very high (1000 x the wild-type level) to very low indeed (eliciting a state of “hypomutation” in which evolutionary change essentially grinds to a halt).

Using this system, we aim to investigate the evolutionary trajectories of P. aeruginosa when challenged with intense selection pressures e.g., in a polymicrobial environment, or upon exposure to antimicrobial agents or nutrient limitation. Project will involve elements of synthetic biology, microbiology, evolutionary biology, modelling and genomics. A stable polymicrobial culture system has recently been developed by the lab and is available for use.  

The brain is a site of relative immune privilege, long considered isolated from the peripheral immune system. We recently identified a population of resident T cells in the healthy mouse and human brain, important for the maturation of microglia (Pasciuto et al, Cell 2020). By analysing the kinetics of migration between the blood and brain, we found that the key bottleneck controlling the number of anti-inflammatory regulatory T cells in the brain was the high rate of cell death the cells exhibit when housed within the brain. Through developing a unique tool, with potential therapeutic application, we were able to deliver a biologic directly to the brain and enhance the size of the regulatory T cell population. The approach protects mice from brain damage following traumatic brain injury, stroke and multiple sclerosis. In this project we wish to explore the immunological processes that drive damage during neuroinflammation, and to harness immune-modulating biologics to prevent damage to the brain. 

Despite recent improvements in population health and prevention, heart failure prevalence and mortality are stagnant overall, with a disproportionate burden in Black, Hispanic and South Asian populations.

Single centre studies provide highly phenotyped populations covering genomics, metabolomics, advanced imaging and longitudinal health trends. In contrast large centralized healthcare data covers decades of hospital admissions and mortality for millions of people, with this data growing in depth, richness and complexity. Collaborations that leverage both approaches have the unique potential of providing needed new insights in the poorly understood heart failure syndrome.

Using advanced cardiac magnetic resonance imaging capabilities and novel biomarkers (NIH), we will conduct deep phenotyping in a diverse cohort of patients with heart failure to elucidate disease phenotypes and differences between races. At a national level (University of Cambridge) we will look at equitability of access to advanced imaging (such as MRI) and interventions (implantable defibrillators) and the impact of these on health outcomes.

Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of cardiovascular diseases such as atherosclerosis, which cause heart attack and stroke. In healthy vessels, VSMC contraction regulate blood flow and blood pressure but loose their contractile function and undergo extensive transformation upon vasuclar insult. This process results in the generation of a wide spectrum of phenotypically changed cells within atherosclerotic lesions, which are predicted to impact differently on disease progression. Using clonal lineage tracing in mouse models of atherosclerosis, we demonstrated that disease-associated cell accumulation result from extensive proliferation of a small subset of VSMC that can generate the full range of distinct cells. By combining lineage tracing with single cell RNA sequencing (sc-RNAseq) in mouse models, we have identified signatures of VSMC-derived cells subpopulations. Interestingly, cells displaying mesenchymal stem cell character are rare in healthy vessels and their numbers increase in disease models. The aim of this project is to understand how specific VSMC-derived cell populations in human disease arise, using a combination of genomics and functional assays, in order to allow efficient cell targeting in atherosclerotic lesions.

The human placenta is the first organ of the embryo and it is functional immediately after implantation. Before fetal organogenesis, the placenta holds a multi-functional and unique role as a physical, chemical, and cellular barrier. It alone orchestrates the chemical communication between mother and fetus. Most of this communication is mediated by the secretion of specific placental peptide hormones (hCG, hPL, etc.) into the maternal bloodstream. Despite these hormones having developmental and irreplaceable functions, little is known about their intracellular life: synthesis, intracellular traffic, secretion, and degradation. More importantly, many pregnancy disorders are associated with lower expression and levels of these hormones in circulation, such as fetal growth restriction and preterm birth. The cell biology of these diseases is not well understood.

With the recent advance in human placenta organoid development and novel culture techniques of trophoblasts derived from stem cells, we can now finally interrogate the fundamental questions about placental hormones' intra and extra-cellular fate. In combination with the diverse set of advanced imagining methods available between the co-mentors of this project (advanced fluorescence and cryo-electron microscopy), innovative multi-omics techniques, and advanced biochemistry and cell biology approaches, we propose to 1) discover the diversity of secretory granules (SGs) expressed in and secreted from the human placenta; 2) implement a novel in vitro secretomics approach to determine the molecular machinery that regulates the secretion of the SGs and their content; 3) validate the mechanisms using human placenta and isolated trophoblasts from donated tissue and new placenta organoids culture.

The successful candidate will have the opportunity to train on several modern imaging techniques and learn about the fundamentals of placenta development and physiology while using a multi-disciplinary approach in a team of expert cell biologists from both institutions and generating impactful basic and applied research.

Adolescence and early adulthood are important developmental periods when young people develop health-related habits that are likely to persist through their adult life. This is also a period when health inequalities emerge, as young people finish their education and enter the labour market, developing their individual socioeconomic position. Improving our understanding of the factors that contribute to the development of diet, related health behaviours, and health inequalities over this life stage will help to identify targets for public health policy and intervention.

We currently know little about the factors which influence changes in health behaviours over the transition from secondary education into further education and employment. This PhD project will focus on this question through analysis of data from the US-based NEXT Generation Health Study and from the UK-based DEBEAT study, applying epidemiological methods to assess changes in health behaviours (diet, physical activity and sleep) through adolescence and early adulthood, analyse dynamic relationships between different behaviours, and investigate how differences in these patterns of development between different groups of the population contribute to health inequalities.

Maternal over-nutrition and obesity during pregnancy is known to have long-term effects on the health of the offspring, including increased risk of obesity. Weight gain in offspring exposed to maternal over-nutrition is at least in part caused by hyperphagia- implicating altered function of hypothalamic energy homeostatic pathways as an underlying cause- but the precise mechanisms by which the in utero environment impacts on hypothalamic development is unclear. Key metabolic hormones such as insulin, leptin and ghrelin have a dual role during brain development as growth factors. These metabolic hormones are altered in an obese pregnancy, providing a direct route by which the maternal nutritional state can impact on offspring hypothalamic development. We will use a combination of in vivo manipulation of hormone levels (e.g. fetal brain injection) and ex vivo neuro-developmental techniques (e.g. neurospheres) to examine the consequences of altered metabolic hormone levels for early hypothalamic development. We will also use immunofluorescence and viral tracing to study hypothalamic architecture in the offspring of obese mothers once they reach adulthood, and correlate the anatomy with functional readouts of complex feeding behaviours using operant and metabolic chambers.

During pregnancy, nutrients must be supplied to the fetus for growth but also to the mother to maintain the pregnancy. This nutrient balance depends on the placenta, an organ that develops during pregnancy to transfer nutrients to the fetus and that secretes hormones into the mother with metabolic effects. Impaired placental function disrupts the materno-fetal nutrient balance and results in major pregnancy complications, including abnormal birthweight with both immediate and long-lasting effects on offspring health. However, our understanding of the importance of placental endocrine function in the control of fetal growth and long-term health of the offspring is unknown. To address this knowledge gap, we have developed new and robust models of genetically-induced placental endocrine malfunction in mice. Using these models, we have found that placental endocrine malfunction is associated with programmed changes in insulin and glucose handling of both the female and male offspring in adult life.

This PhD will extend these important findings by:
1. Identifying which tissues in the offspring are affected by placental endocrine malfunction and responsible for the altered glucose and insulin handling of offspring in later life.
2. Exploring the intrauterine mechanisms by which metabolic organs of the developing offspring are programmed by placental endocrine malfunction.

This will be achieved by studying the function of key metabolic organs in female and male offspring that were supported by placentas with endocrine malfunction. Particularly, it will use genetic manipulation and a range of in vivo physiological (metabolic testing, NMR scanning), and in vitro molecular (respirometry, RNAseq, western blotting, qPCR, epigenetic analysis), histological and biochemical assays.

Antiviral restriction factors (ARF) are a critical element of cellular innate immunity, representing the first barrier to viral infection that can determine outcome. We aim to identify and characterise novel ARF and their viral antagonists, since therapeutic interruption of viral antagonism can enable restoration of endogenous antiviral activity.

We employ a number of human pathogens, in particular Human Cytomegalovirus (HCMV), Monkeypox virus (MPXV) and its vaccine, Modified Vaccinia Ankara (MVA). Our systematic proteomic analyses determine which cellular factors each pathogen targets for destruction, since we have shown these to be enriched in novel ARFs. For example, we recently developed a multiplexed proteomic technique that identified proteins degraded in the proteasome or lysosome very early during HCMV infection (Nightingale et al, Cell Host & Microbe 2018). A shortlist of 35 proteins were degraded with high confidence, and we have since shown that several are novel ARF, with characterisation of these factors forming ongoing projects. Application to MVA infection indicated further candidates, and identified novel mechanisms of vaccine action (Albarnaz et al, in review, https://www.researchsquare.com/article/rs-1850393/v1). Furthermore, interactome screens can identify the viral factor(s) responsible for targeting each ARF, and indicate mechanism (Nobre et al eLife 2019).

This project will now identify and characterise critical pan-viral ARF, which can restrict diverse viruses. For the most potent, we will determine both the mechanism of restriction and the mechanism of virally mediated protein degradation. In order to prioritise the most important factors, there will also be the opportunity to use novel multiplexed proteomic screens.

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.

We mainly study how mitochondrial dysfunction and mutations in the mitochondrial genome affect neural stem cell behaviour in Drosophila and mouse. The questions we address are:
(1) how mitochondrial dysfunction affects normal and pathological cell fate decisions in the developing brain. We previously showed that neural stem cells in the brain rely heavily on mitochondrial energy production and now study how they interact with the glial cells that make up their stem cell niche.
(2) how transcription of the nuclear genome is regulated when a cell is confronted with mitochondrial dysfunction. We employ and develop innovative DamID-based in vivo chromatin profiling technology to study metabolism of chromatin modification.
(3) how mutations in the mitochondrial genome evolve over time, during brain development and aging. We use in situ hybridisation-based methods and single-cell CRISPR screening to identify novel regulators of mitochondrial genome maintenance.

In order to study these questions in an in vivo context, in (stem) cells surrounded by their appropriate tissue environment, our primary model system is the fruit fly, Drosophila melanogaster. In addition, we actively translate our findings and the technology we develop into mammalian model systems, in particular the mouse embryonic cortex.

Relevant references
- van den Ameele J, Krautz R, Cheetham SW, et al., Reduced chromatin accessibility correlates with resistance to Notch activation. Nat Commun. 2022;13(1):2210.
- 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.
- van den Ameele J, Brand AH. Neural stem cell temporal patterning and brain tumour growth rely on oxidative phosphorylation. eLife. 2019;8:e47887.
- Tiberi L*, van den Ameele J*, Dimidschstein J, Piccirilli J, Gall D, Herpoel A, Bilheu A, Bonnefont J, Iacovino M, Kyba M, Bouschet T, Vanderhaeghen P. Bcl6 induces neurogenesis through Sirt1-dependent epigenetic repression of selective Notch targets. Nat Neurosci. 2012 Dec;15(12):1627-35.
- Gaspard N, Bouschet T, Hourez R, Dimidschstein J, Naeije G, van den Ameele J, Espuny-Camacho I, Herpoel A, Passante L, Schiffmann SN, Gaillard A, Vanderhaeghen P. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature. 2008 Sep 18;455(7211):351-7.

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.

This project will be co-supervised by Prof. A. Quaegebeur.