PhD Studentship (Basic)

Characterising the evolution and development of vertebrate nervous systems using cross-species comparative genomics.  The human brain is enormously complex, consisting of billions of cells, diverse cell types and complicated connectivity. One approach to understand such a complex system is to study instances in more primitive organisms, where homologous cell types and developmental processes can suggest how particular components of the brain may have originated, what purpose they serve and how they function. In this project, I aim to use single-cell RNA sequencing (scRNA-seq) datasets from multiple species to identify homologies across vertebrate and invertebrate nervous systems. To achieve this, I aim to improve existing methods for comparing, integrating and visualising cross-species genomics data, for which current solutions either do not exist or are unsuitable. This will include approaches for identifying gene orthologs, normalising expression levels, matching cell types and, perhaps most challenging, identifying equivalent developmental stages. This research will lead to greater insight into the evolution of neural cell types, gene regulatory networks and neurodevelopmental processes across species and provide general resources for comparative analysis of transcriptomics datasets. These resources may have a wider impact on other areas of biology and medicine, such as in cancer research, for which the same tools may be used, for instance, to compare transcriptomes across cancer samples.


PhD Studentship (Basic)

The role of HIF2α in non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD), marked by fat accumulation (steatosis), inflammation and scarring of the liver, affects about one third of people. There are no specific treatments available.
We believe the activation of a component of the hypoxia response, HIF2alpha, contributes to this disease. HIF2alpha responds to hypoxia (low oxygen levels) in part by limiting the capacity of mitochondria to burn fat, an oxygen demanding process. In the liver, this reduced fat oxidation could contribute to steatosis in NAFLD.
We will investigate this using mice that lack HIF2alpha in their livers. These will be fed a diet that induces NAFLD. We will measure metabolic features, such as fuel oxidation, and disease severity to determine whether interfering with HIF2alpha increases fat oxidation in NAFLD, and whether this improves disease severity. We will also investigate what activates HIF2alpha in NAFLD using cell culture approaches.

Finally, we will investigate treatment options for NAFLD that target HIF2alpha. Some of these options are already in clinical trials for other diseases and could be adapted for NAFLD treatment.
With this project, we aim to increase our understanding of the harmful processes involved in a very common disease, and use this to explore novel treatment avenues.

Grants awarded from 1 October 2005 to 30 June 2021

Creative Commons Attribution 4.0 International (CC BY 4.0)


PhD Studentship (Basic)

Epigenetic signatures of inflammation in relation to brain structure and connectivity across the lifecourse How does chronic inflammation affect brain structure and connectivity as we grow older, and what aspects of our lifestyle influence this? We know that inflammation affects the function and integrity of the brain, with adverse outcomes in both development and older-age. Chronic, low grade inflammation is usually assessed by measuring the levels of various proteins in the blood, yet these measures provide only a snapshot of inflammatory exposure. A more reliable indicator may arise from DNA methylation, an epigenetic modification that is influenced by both genes and environment, and is involved in the regulation of gene expression. Using three distinct cohorts (age ranging from newborn (


PhD Studentship (Basic)

Oligodendroglial Dysfunction in Huntington's Disease Huntington’s disease (HD) is a genetic neurodegenerative disease causing long term disability and life-threatening complications. It is well known that the loss of particular types of nerve cells in the brain causes the main symptoms of HD, but there is evidence that a different type of brain cell, oligodendrocytes, are also involved. Recent evidence has shown that human oligodendrocytes are heterogeneous, suggesting that their functions vary and that these are altered in disease. In this project I will investigate whether oligodendrocyte states are different in HD. I will analyse and validate the heterogeneity of oligodendrocytes in post mortem brain tissue from HD patients, as well as in oligodendrocyte cultures generated from human stem cells. Furthermore, I will investigate whether certain dysfunctional oligodendrocyte states are shared across different diseases by comparing the heterogeneity of oligodendrocytes in HD and Multiple Sclerosis. Finally, I will investigate whether targeting the cause of HD, a mutation in the huntingtin gene, can change oligodendrocyte states to become more like healthy cells. Together these approaches will establish whether and how oligodendrocyte dysfunction is a pathological feature of HD and will provide insight into common oligodendrocyte states across disease.


PhD Studentship (Basic)

Regulation and function of RNF12 E3 ubiquitin ligase in Tonne-Kalscheuer Syndrome (TOKAS) Background: Intellectual disability comprises a series of poorly understood neurodevelopmental disorders affecting around 1-2% of the general population. Tonne-Kalscheuer Syndrome (TOKAS) is an intellectual disability syndrome caused by mutations in the RNF12/RLIM gene, which encodes an E3 ubiquitin ligase that tags specific proteins for destruction in a process called ubiquitylation. In order to understand TOKAS disorder, the signals that control RNF12, the proteins it ubiquitylates and the cellular processes RNF12 governs must be identified.

Approach: RNF12 is controlled by a chemical switch known as phosphorylation. My recent work uncovered a new function for a protein kinase called Aurora in phosphorylating RNF12. I will now use biochemistry and cell biology to study how Aurora phosphorylation of RNF12 controls protein ubiquitylation. I will then employ genome-editing technology and stem cell models to explore the impact of Aurora-RNF12 signalling on gene expression and development of the brain and genitals, which is disrupted in TOKAS patients. Finally, I will use proteomic technologies to search for new proteins that are ubiquitylated by RNF12, as these may be relevant to the development of TOKAS.

Impact: These studies will provide new insight into regulation and functions of RNF12 protein ubiquitylation that are disrupted in TOKAS intellectual disability.


PhD Studentship (Basic)

The structure, function and essentiality of Trypanosoma cruzi mitochondrial fucosyltransferase The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are the causative agents of neglected tropical diseases. They rely on surface glycans, chains of sugar units attached to proteins and lipids, for their survival and infectivity. These surface glycans are synthesized by enzymes called glycosyltransferases located in the secretory pathway. However, contrary to this canonical model of glycan synthesis and surface expression, our group has recently described the presence of an essential glycosyltransferase, a fucosyltransferase, in the mitochondrion of T. brucei. A similar putative fucosyltransferase gene, called TcFUT1, has been found in the genome of T. cruzi, the causative agent of Chagas’ disease, endemic in the Americas. We aim to obtain recombinant, active TcFUT1 protein in order to analyse its enzymatic activity, define its preferred substrate(s) in vitro, design assays for compound screening and to raise antibodies against it for immuno-localisation. In parallel, we also aim to define its essentiality and characterise its endogenous substrates. This work will provide an opportunity to uncover the function(s) of this novel mitochondrial fucosyltransferase and provide a much-needed drug target for Chagas’ disease.


Discretionary Award – C&S

Strengthening research ethics systems in Latin America and the Caribbean Strengthening research ethics systems in Latin America and the Caribbean

This proposal of the Regional Program on Bioethics of the Pan American Health Organization (PAHO) aims at significantly improving the regional research ethics landscape and, specifically, at strengthening research ethics systems and enhancing ethics preparedness to conduct research during emergencies. In response to a 2018 explicit request from the countries in the Americas to advance research ethics with a systemic approach, PAHO’s Regional Program on Bioethics developed indicators and a strategy to address the regional challenges. While this action has already triggered progress rapidly in few countries (e.g. Peru), PAHO’s resources to scale up these efforts as requested by the countries are very limited. This grant would allow PAHO to (a) assess the current situation using indicators, (b) advance change in several countries in Latin America and the Caribbean using national research ethics policies as a strategy, (c) support the implementation of such policies through an online tool for ethics review, and (d) share this model so it can be replicated by other regions. PAHO is uniquely positioned to achieve these outcomes due to its ongoing work supporting national health authorities on bioethics.


PhD Studentship (Basic)

Mechanisms of cell fate plasticity in adult CNS progenitors Myelin sheaths provide trophic support to the axons and are essential for rapid nerve impulse conduction, so maintaining their integrity is of utmost importance. In response to demyelinating injuries in the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) classically differentiate into oligodendrocytes, which make new myelin sheaths. However, lineage tracing studies have demonstrated that OPCs can also generate Schwann cells (SCs), the myelinating cell of the peripheral nervous system. This is surprising because the progenitors that produce SCs and OPCs separate very early during development, so SCs are considered phylogenetically distinct from OPCs. Therefore, I aim to investigate the transcriptomic mechanisms that underlie this unusual cell fate, and to characterise the functional consequences of SC versus oligodendrocyte myelination in the CNS. I will impose a SC identity onto OPCs using CRISPR/Cas9 gene editing to manipulate the activity of core transcription factors, Olig2 and Sox10, then I will use histological, behavioural and sequencing studies to evaluate the functional impact of Schwann cell myelination in vitro and in vivo. These findings will reveal insights into the mechanisms of OPC cell fate decisions and could represent a new therapeutic approach to promote remyelination.