Research Opportunities

Viruses are obligate parasites that have evolved to manipulate their host to their advantage. Chronic viral infection of the liver is a global health problem, with over 300 million individuals infected with hepatitis B (HBV) or C (HCV) virus that causes liver disease which can progress to liver cancer. Viral hepatitis-related liver disease is the number 4 disease-related killer worldwide and is associated with more than 1 million deaths/year, highlighting an urgent need for new curative treatments. We recently discovered that low oxygen environments, naturally found in the liver, enhance HBV replication at several steps in the viral life cycle. Similar condition may apply to HCV replication. Cellular response to low oxygen is regulated by a family of oxygenases and hypoxia inducible factors (HIFs) that control genes involved in energy metabolism and other cellular processes. This project will study the role of hypoxic signaling and related metabolic pathways in HBV or HCV replication and their impact on pathogenesis, immune based and epigenetic therapies.

The successful candidate will investigate the molecular mechanisms underlying these observations. In particular, we will (i) identify the role of HIFs in HBV cccDNA biogenesis, transcription and metabolism, and production of infectious particles, and conduct comparative studies in HCV replication (ii) analyze how these host-virus interactions are shaped by the tissue microenvironment, genetic manipulations and metabolic parameters. The project has basic and translational research components and applies state-of-the-art technologies, tools and model systems to study HBV infection and its mechanism of disease. Taken together, this exciting project builds on strong preliminary results and existing expertise that may lead to new therapeutic targets and antiviral development.

*This project is available for the 2021 Oxford-NIH Pilot Programme*

This project aims to determine how changes in blood glucose can affect hunger and the drive to feed and examine how this can be altered in conditions such as diabetes.

Hypoglycaemia (low blood glucose) is a complication of the treatment of diabetes with insulin. It is feared by people with diabetes and is associated with increased risk of death. One of the important defences against a falling blood glucose is the generation of hunger- a potent defence which both warns and directs towards corrective action to help restore blood glucose. A subset of people with diabetes develop defective defensive responses to and warning symptoms (including hunger) of hypoglycaemia. This puts them at a markedly increased risk of suffering severe episodes of hypoglycaemia.

We want to determine how hypoglycaemic feeding is triggered and the mechanisms by which this may become altered in diabetes. To examine this in murine models, we will combine the skills of Evans’ laboratory (hypoglycaemia, insulin clamp methodology, operant conditioning feeding assessment) located within the Institute of Metabolic Science with broader interest and expertise in appetite and feeding with Krashes’ laboratory (neurocircuitry of feeding) to examine how and where glucoprivic feeding maps onto both conventional feeding pathways and also the neurocircuitry which triggers other counter-regulatory responses to hypoglycaemia. The student will examine how this adapts after exposure to antecedent hypoglycaemia. Finally, they will examine potential therapeutic targets to boost/ restore or prevent the loss of protective hunger in diabetes with recurrent hypoglycaemia.

Regulatory T cells expressing the FoxP3 transcription factor (Tregs) are arguably the most important naturally-occurring anti-inflammatory cells in the body and are prime candidates for cellular therapy of autoimmunity and transplant rejection. They are potently immunosuppressive, indispensable for maintaining self-tolerance and in resolving inflammation. Tregs can be induced to develop dichotomously from naïve precursors that also have the ability to differentiate into inflammatory T cell lineages. The choice of differentiation pathway (“fate decisions”) is directed by environmental signals and interplay between many transcription factors working within networks. The expression of many genes is required for a healthy immune response and this is highlighted by the discovery of many gene mutations that are associated with very early onset auto-immune disease.

Our goal is to understand how transcriptional signals from the environment are integrated in T cells to determine inflammatory versus regulatory T cell differentiation and the quality and duration of effector function. Experimental approaches will involve genomics of patients with primary immuno-deficiencies and very early onset colitis, next generation sequencing platforms (RNA-seq, ChIP-seq, Cut&Run, ATAC-seq, scRNAseq), molecular and cell biology, CRISPR genome editing and in vivo murine models.

Humans and animals adjust their feeding behaviour according to many environmental factors, including the spatial context where food is found and consumed. Such contextual control of food seeking and eating is notably central to the ability to meet future needs and maximise chances of survival to changes in feeding routines but their underpinning brain network mechanisms and pathways remain unclear. The Dupret laboratory (MRC Brain Network Dynamics Unit at the University of Oxford) investigates how the concerted spiking activity of neurons supports memory and the Krashes laboratory NIH/NIDDK) investigates homeostatic and non-homeostatic feeding behaviour. An integrated project between the two labs, in collaboration with an NIH OxCam Scholar would be designed to enable the pursuit of an Ph.D. revealing circuit mechanisms of contextual control of feeding behaviour using in vivo large-scale network recordings in behaving rodents, combined with optogenetic and closed-loop optogenetic manipulations.

Germline genomes are immortal.  Their genetic information is transmitted to the next generation and ensures that continuation of life.  To protect the integrity of their genomic information, germ cells employ a specialized small RNA-based defense system, PIWI-interacting small RNAs (piRNAs) and their PIWI protein partners.  The interest of the Karam Teixera lab in germ cell biology and evolution and the focus of the Haase lab on mechanisms of small silencing RNAs converge on piRNA-guided surveillance of genome integrity. The collaborative project of an OxCam Scholar is designed to combine strength of both labs in genetics, biochemistry and genomics, and offers training in experimental techniques and basic computational analyses of next-generation sequencing data.  Results from this graduate study will further our understanding of how germ cells ensure genome integrity and the survival of future generations. 

Alzheimer’s disease is the most common neurodegenerative disease. It affects millions of individuals worldwide. Because of large scale genomic studies, we know a number of genetic risk factors that increase the risk for disease. We also know a few factors that promote resilience to disease onset. The Narayan lab seeks to identify, understand, and modulate the cellular pathways that underlie risk and resilience to Alzheimer’s disease.  We do this with the goal of developing new therapeutic or preventative strategies for neurodegenerative diseases. To accomplish our research goals, we use a combination of genetics, biochemistry, molecular biology, and human induced pluripotent stem cell (iPSC)-derived neuronal and glial cell types. We’re excited to welcome new team members interested in studying the cell biology behind neurodegenerative disease risk.

The goal of our research is to understand how cells use various protein quality control (PQC) strategies to eliminate misfolded proteins, and how defects in these processes lead to aging-associated neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Specifically, we study the molecular mechanisms underlying protein translocation-associated quality control at the endoplasmic reticulum (ER), the export of misfolded proteins via unconventional protein secretion, and cell-to-cell transmission of misfolded alpha-Synuclein and Tau aggregates. We envision that a thorough characterization of these protein quality control systems may one day improve both diagnosis and treatment of aging-associated neurodegenerative diseases.

Unusual RNA/DNA structures (R-loops) are formed when the RNA hybridizes to a complementary DNA strand, displacing the other DNA strand in this process. R-loops are formed in all living organisms and play crucial roles in regulating gene expression, DNA and histone modifications, generation of antibody diversity, DNA replication and genome stability. R-loops are also implicated in human diseases, including neurodegeneration, cancer mitochondrial diseases and HIV-AIDs.

Collaboration between Prof Crouch (NIH) and Dr. Gromak (Oxford) labs will focus on understanding the regulation of R-loops and uncover the molecular mechanisms which lead to R-loop-associated diseases. We will employ state-of-the-art techniques including CRISPR, Mass Spectrometry and molecular biology approaches to understand the principles of R-loop biology in health and disease conditions. In the long term the findings from this project will be essential for the development of new therapeutic approaches for R-loop-associated disorders.

*This project is available for the 2021 Oxford-NIH Pilot Programme*

The project will use X-ray crystallography, cryoEM, microbial genetics and molecular biology to explore how small RNAs and small proteins act as regulators with speed and precision in diverse bacteria.

Neuronal plasticity is fundamental to nervous system development and function. We have recently discovered that reactive oxygen species (ROS), known for their destructive capacity in the ageing or diseased brain, function as second messengers for implementing structural plasticity at synaptic terminals. Moreover, different sources of ROS (cytoplasmic vs mitochondrially generated) regulate genetically distinct aspects of synapse development (growth vs release site number). Do ROS sculpt synapse plasticity in response to the metabolic state of neurons? How does ROS signaling intersect with other signaling pathways regulating synaptic plasticity, such as BMP and Wnt? This project will combine biochemical and genetic approaches with electrophysiology and methods for live and super-resolution imaging to investigate the contribution of various signaling pathways to synapse plasticity. We expect this project to redefine our understanding of how multiple signaling pathways integrate at the synapse to regulate distinct elements of plasticity.

Undertake genomic and epigenomic studies into the mechanisms of tumorigenesis in individuals with inherited predisposition to neuroendocrine tumor syndromes, especially pheochromocytoma/paraganglioma associated with mutations in the Krebs cycle. Such discoveries can lead to understanding of developmental and other mechanisms in these tumors related to the same syndrome but behaving in a different way and occurring in different tissue of origin. Such data can be paramount to study novel therapeutic approaches for these tumors based on the discovery on novel tumor-specific targets as well as biomarkers.

Some of the most globally impactful diseases are caused by emerging and re-emerging viral pathogens. We have a long-standing collaboration with Vincent Munster at the NIH, investigating disease pathogenesis and developing vaccines against a number of outbreak pathogens.
 
This project represents an opportunity to join this world-class team to advance these works, investigating the mechanisms of disease, deriving correlates of protection, testing new therapeutic interventions and deriving structural determinants of disease through collaboration with Prof. Thomas Bowden.

Influenza A virus imposes a significant socio-economic burden on humanity.  Vaccination is effective in only 60% of individuals, even under optimal circumstances.  The difficulty stems from the remarkable ability of influenza A virus to evade existing immunity.  IAV’s error prone polymerase enables the rapid antigenic evolution of the two virion surface glycoproteins, neuraminidase (NA) and hemagglutinin (HA).  Since the most potent antibodies (Abs) at neutralizing viral infectivity are directed the HA and NA globular domains, amino acid substitutions in these regions enable IAV to evade Ab-based immunity.  The project focuses on understanding the “immunodominance” of Ab responses to HA and NA in humans.  Immunodominance describes the strong tendency of the immune response to respond to complex antigens in a hierarchical manner, with higher ranking, “immunodominant” antigens potentially suppressing (“immunodominating”) responses to “subdominant” antigens.  By focusing responses on single antigenic sites, it is likely responsible for enabling influenza A virus to evade immunity by allowing the virus to sequentially alter its antigenicity.