Research Opportunities

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.

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.

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.

The impact of proteins and their modification on disease states is now being recognized as crucial, but there are knowledge gaps that have to be filled to develop therapeutic agents to combat disease. Focusing on infectious diseases using mutant cell lines, mouse models and patient data we will study the link between PTM status and subcellular location which has been so far poorly captured in the majority of experimental workflows. The knowledge of the PTM affecting relocalization of the protein and, in turn, its function, may be pivotal to the correct drug design. This project combines development of state of the art quantitative proteomics methodologies, computational workflows and whole cell modelling which will be used to decipher the mechanism of immunity to infection and propose new ways of treatment.

The metabolic repertoire of immune cells – which encompasses metabolic enzymes/pathways, the available nutrient sensors and metabolic checkpoint kinases, and the epigenetic programming of metabolic genes – directly enables and modulates specific immune functions. Capitalizing on a large cohort of patients suffering from rare genetic immunodeficiency that have been whole-genome sequenced, our goal is to delineate the genetic and molecular basis of how cellular metabolism regulates immune-function in human health and disease states. Experimental approaches will involve genomics, molecular biology, cell biology, immunology, and biochemistry with an aim to elucidating mechanisms that lead to new treatment approaches to inborn diseases of immunity.

Malaria remains an important global health problem; with increasing drug resistance and the lack of an effective vaccine, new therapies are needed and should be based on a rigorous understanding of parasite biology. Our NIAID lab has used a multidisciplinary approach to discover and characterize the three known ion channels in bloodstream malaria parasites. Through academic and pharmaceutical collaborations, we have also found potent inhibitors that are being pursued as new antimalarial drugs. Research projects will be tailored to the interests of the trainee and expertise available in possible collaborator labs. These projects may utilize molecular biology including CRISPR and heterologous expression, structural biology including cryoEM, biochemical methods including electrophysiology, epigenetics, and high-throughput screening for drug discovery.  These and other methods are actively used in the lab. Dr. Desai has collaborators at Oxford, Cambridge, and Wellcome Sanger, depending on project.

Hematopoiesis is a finely tuned process by which mature blood cells of multiple lineages are constantly generated throughout life from hematopoietic stem cells. In humans, definitive hematopoiesis commences in the fetal liver (FL) at around five weeks of gestation, and remains the main site of hematopoiesis throughout fetal life. Hematopoiesis in the bone marrow (BM) starts around 11-12 weeks of gestation, but does not take over as the primary site of hematopoiesis until just after birth. Recent evidence suggests that fetal hematopoiesis is distinct from postnatal hematopoiesis in many ways. Most of these studies have been done on mouse models, but whether these differences exist in, or are a true reflection of hematopoiesis in the human setting, remains to be determined. We, and others have begun to investigate unique features of human fetal hematopoiesis and this project will determine fetal specific programmes that change through ontogeny. This may depend on the physiological processes or demands of that particular developmental stage, and/or in response to specific microenvironmental cues. This research is clinically relevant since the transplantation of hematopoietic stem cells from donors of different ages vary in their regenerative and differentiation potential. Studying hematopoiesis throughout the human lifespan may be important not only to understand normal developmental processes, but also to understand the pathogenesis of postnatal haematological diseases that may have their origins in fetal life. Research by the Roy laboratory particularly focuses on properties of fetal cells that contribute to leukemia initiation in utero and how these might change after birth, and we have recently developed a unique infant acute lymphocytic leukemia (ALL) model. We are particularly interested in ‘oncofetal’ genes that might define the biology of infant and childhood leukemias; and whether they can be manipulated for therapeutic interventions.

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

A previous infection with one of the four dengue viruses increases future risk of severe dengue disease, including hemorrhagic fever, upon infection with a different dengue virus. For this reason, dengue viruses 1-4 are challenging vaccine targets because sub-protective vaccines can increase risk the disease vaccines are designed to prevent. In the Viral Epidemiology and Immunity Unit (Chief, Dr. Katzelnick), we aim to identify correlates of natural and vaccine protection and antibody-dependent enhancement in order to develop better next generation vaccines, extend the longevity of vaccine-induced immunity, and characterize how vaccines may affect viral evolution and transmission.  Our work combines immunology, virology, and epidemiology, including close collaborations with research teams leading longitudinal cohort and vaccine studies in Nicaragua, Sri Lanka, Thailand, Ecuador, the Philippines, and other sites. Specific projects include studying quaternary ‘super-antibodies', which bind epitopes across viral envelope proteins, and testing whether these antibodies provide enduring protection against dengue and other viral diseases. We will also study antigenic evolution away from existing immunity for flaviviruses and coronaviruses. Dr. Katzelnick was part of the NIH OxCam program (2012-2016) and is open to collaborating with research groups at both Oxford and Cambridge to mentor Ph.D. students.