Research Opportunities

There is a pressing need to improve the understanding of morbidity for schistosomiasis. These parasitic blood flukes afflict over 250 million people worldwide with over 700 million people at risk. For Schistosoma mansoni (a species that causes the intestinal form of schistosomiasis), untreated individuals can develop severe or functional morbidities such as enlarged livers/spleens, periportal fibrosis, oesophageal varices, anaemia, and chronic gut inflammation. The onset and progression of these morbidities is a complex interplay of host genetics and immune response, environmental factors, coinfections, and social determinants. This project is an exciting opportunity to combine work in immunology with epidemiology, providing opportunities to apply computational approaches, experimentally test mechanistic hypotheses found in humans in mice, and gain fieldwork experience in global health research. The candidate will gain skills in both wet lab work and fieldwork in Uganda. You will join multidisciplinary labs at the NIH-NIAID and Oxford.

Many pathogens can infect a wide range of potential hosts. Understanding the factors that control pathogen host range is critical for understanding host-pathogen biology and for identifying potential reservoirs of disease. A major determinant of a pathogen’s host range is the compatibility between the pathogen’s effectors and key host proteins, such as host receptors required for infection or host immune proteins whose function the pathogen specifically neutralizes. We are developing and utilizing a new approach to systematically explore which animals carry host proteins that are susceptible to particular pathogen effectors. For a known targeted host protein, we identify thousands of homologs from across the space of sequenced genomes, and then synthesize the surface of the homologs bound by the effector and test whether the effector can bind them.

This project will involve selecting an important human pathogen, such as malaria, HIV, plague, or any other pathogen of interest to the student, and applying our systematic approach to determining its potential host range. We are also interested in exploring other applications of this novel approach, such as testing a single host protein against a range of pathogen effectors to determine the space of potential future pathogens. Please get in touch if you have ideas anywhere in this space!

Creatine is an important energy storage and transfer molecule in muscle and brain but is synthesized primarily in the kidneys and liver. Hence, creatine uptake in skeletal muscle, brain, and heart is dependent on the creatine transporter (CrT or SLC6A8). Loss-of-function mutations in CrT are the second most common cause of X-linked intellectual disability and low tissue creatine levels result in skeletal muscle atrophy and are closely associated with heart failure. Cells down-regulate expression of CrT when creatine levels are high, but the mechanisms underlying this autoregulation and the importance to normal physiology and disease are unknown.

Recently, we found that creatine feedback inhibits translation of the CrT mRNA to control transporter production, and we identified elements in the CrT mRNA that are important for this control. This PhD project will involve molecular genetic analyses to more fully characterize the translational control mechanism(s) by which creatine feedback inhibits its own cellular uptake. In addition, CRISPR-Cas technology will be used to eliminate the translational control mechanisms in mice, and then physiological studies of the mice will be used to characterize the role of CrT autoregulation.

In the last decade alone, degenerative diseases have featured heavily in the ten leading causes of death. Degenerative diseases and injuries have not only seen a marked increase in mortalities but are also the major contributor to the rising disability in our aging populations. As a result, there has been significant interest in developing improved implantable medical devices, which aim to replace, support, and restore the function and mobility lost by diseased tissues.

The extra cellular matrix (ECM) of tissues is an excellent base material for therapeutic and regenerative biomedical devices, since they can mimic the biological, chemical and physical environment experienced by cells in healthy tissue. However, the biomedical devices currently fabricated from the ECM have limited tunability or dynamic control once implanted within the body. The aim of this project is to develop soft robotic biomedical devices from biological polymers. Soft robots are flexible, have a high specific strength and high response rates which make them ideal for applications requiring sensitive motions. Biopolymers are an attractive material choice for biomedical soft robots: they are abundant, biodegradable, and can offer excellent biomimicry if derived from the ECM. However, these polymers typically display limited stimulus-driven shape change on their own.

As part of the project, the student will optimise the electroactivity of tissue-derived biopolymers and eventually develop a proof-of-concept therapeutic device for an application of their interest. Possible applications include (but are not limited to) drug delivery, neural and cardiac stimulators, sensors for cell attachment and proliferation. The project will involve the fabrication and structural characterisation at the nano- and micro-scale, assessment of electrical activity and opportunities for in-vitro/in-vivo testing.

The laboratory of Prof. Bridge in Oxford uses multi-modal MRI to understand the pathways in the human visual system, and how they are affected by vision loss early or late in life.

The laboratory of Dr. Nienborg at the NIH combines behavior, neurophysiology, and videography in mammalian animal models to better understand how the visual system processes information depending on the animal’s behavioral and cognitive state. 

Visual processing during natural behavior requires subjects to distinguish between changes in visual information caused by a subject’s own body movements (e.g. by walking along a street), and those caused by changes in the external world (e.g. a car driving by). How the brain achieves this is fundamental to understanding visual perception. Moreover, the degree to which their own body movements affect processing in visual cortex in normally sighted and blind subjects has direct implications for the development of neural prostheses targeting the visual cortex.

The project will have two objectives:

1. Identify how spontaneous body movements affect processing in the visual cortex in a mammalian animal model during head-free, naturalistic behavior.
2. Compare the modulations in the visual cortex by a subject’s own body movements in sighted and blind human participants.

This project will allow students to learn wireless electrophysiological recordings in mammalian animal models (e.g. non-human primates or a highly visual rodent species) combined with videography during naturalistic behavior. Students will also be able to learn how to leverage recent machine learning approaches for the analysis of the video and neural data. Additionally, students will have the opportunity to learn how to acquire and analyze functional MRI data in sighted and blind human subjects, using a variety of tools.  

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. 
 

Our research group aims to understand hypertensive disease progression of women and their children following pregnancy complications, such as hypertensive pregnancy and preterm birth, to identify optimal approaches to reduce long term risk. This includes development of new clinical tools to identify, track, and slow the disease progression as well as novel interventions.

This project will apply computational modelling and machine learning to large scale imaging datasets to study disease progression related to a hypertensive pregnancy across multiple modalities and organs. The insights into key structural and functional changes at the organ-level that describe stages of disease will be used to identify potential intervention targets.

Furthermore, we will use imaging data collected within our ongoing clinical trials to help us understand how interventions modify the underlying disease development and how this could be incorporated in clinical practice to transform long-term patient outcomes after a hypertensive pregnancy.

Our group works to enable health research in diseases, communities and settings where evidence to enable prevention, treatment and management of devasting burdens to health are woefully lacking. Our research sets out to understand how research methods, processes, skills and implementation could happen better, and be locally-led, in the most underserved regions across the globe. Our approaches are typically participatory, mixed-methods action research. This could be exploring health research study design, or how to work with the community to tackle perceptions about research and how to overcome these.

We work with health research teams and health workers across Africa, Asia and Latin America and work together to look closely at the challenges they are experiencing in the design, set-up, operational delivery and reporting of their research. We seek to work with them to identify better methods and approaches. We work in delivering skills training and capacity development and we also use digital technology and want to use advances in machine learning to drive equity in access to knowledge so that researchers, wherever they are, have access to the same quality and volume of training and resources.

Undertaking a DPhil with us could involve clinical trial design, or the application of AI in healthcare. It could have a social science or health economic component. Our DPhil projects always involve working in partnership with our collaborators in the Global South, and therefore travel and capturing data in those settings would be very likely. All our research is about tackling the inequity about where health research happens, who leads and who benefits from the data.

What sets the brain apart from other organs is its complex connectivity. In order to study brain function, we need techniques for measuring brain connections with high precision in living humans. The goal of this project is to develop new methods for measuring brain connections using magnetic resonance imaging (MRI).

The project focuses on the cortex, a thin sheet of grey matter surrounding the brain. The cortex is well developed in primates, particularly humans, and plays a key role in cognition. It has a characteristic layered structure; each layer containing different varieties of neurons and connections. The input and output of a cortical region is determined by the connections of the layers. Thus, measuring layer connectivity can give us key insight into information flow in the brain. But these detailed anatomical patterns have only been studied in animal brains, where it is possible to precisely delineate connections.

This project aims to develop new methodology to study layered connectivity in the human brain using MRI. The incredible flexibility of MRI allows us to sensitise the measured signals to multiple aspects of tissue microstructure. We will use this flexibility to create MRI measurements that are sensitive to cortical lamination and integrate these measurements with computational models of laminar connectivity.

This project will open the door to addressing new questions about human brain organisation, such as whether brain areas are organized hierarchically, how information flows across the brain during cognition, learning, and memory; and what happens in diseases that disrupt brain connections

Regulatory T cells (Tregs) have the ability to suppress allogeneic immune responses and have therefore become interesting as a possible cellular therapy.  Our group is leading a phase II randomised clinical trial utilising Tregs as a cellular therapy for kidney transplant recipients.

The proposed project aims to in depth investigate the local immune response within the transplanted allograft, specifically focusing on infiltrating regulatory T cells and their local interactions with other infiltrating immune cells, utilising renal biopsy samples from the cell therapy trial.  We hypothesise, that cellular therapy with regulatory T cells will result in trafficking of the Tregs cells to the allograft and creation of a local tolerogenic microenvironment.

We are proposing to utilise our unique collection of Treg treated patients’ biopsy samples employing the cutting-edge technology of spatial transcriptomics and single cell RNA sequencing to determine the cellular and molecular composition of leukocyte infiltrates in allograft biopsies, dissect cellular interactions in situ and determine Treg homing to the allograft.

The human microbiome is important for many aspects of our health and yet we currently lack the ability to modulate it for the vast majority of diseases. The key challenge is that it is a diverse ecological system, containing many strains and species of microbe, which needs new approaches and paradigms for the treatment of disease. This project will culture diverse anaerobic species of gut bacteria alongside bacterial pathogens to look for species combinations that can prevent or treat disease. The core methods will involve bacterial culture in the lab, but also germ-free mouse work to validate discoveries. A combination of ecological and evolutionary approaches will be applied to help rationally design multispecies communities that both treat disease but also avoid the evolution of resistance in pathogens. In this way, the goal is to help usher in a new set of treatments for microbiome-based diseases and reduce our reliance on antibiotics.

Most translational efforts for uncommon cancers stem from oncogenic mutations identified by sequencing. In contrast to genomic analyses, the tumor proteome has the potential to better approximate phenotype-inducing alterations, particularly in the absence of targetable driver mutations. However, tumor analyses using mass spectrometry can be challenging. Exosomes (small extracellular membrane-enclosed vesicles) may circumvent these issues and serve as a valuable, prioritized, “window” into the tumor cell proteome. Applying this reasoning to bile duct cancers (cholangiocarcinoma, CCA), we performed mass spectrometry on exosomes extracted from patient bile, revealing a 17-fold enhancement of the nuclear export protein XPO7. Immunohistochemistry analysis of XPO7 expression in 318 CCA patients unexpectedly demonstrated intense cytoplasmic staining. Within the cytosol we demonstrate that XPO7 exists in a molecular complex with the serine/threonine kinase SLK. shRNA-mediated knockdown of either XPO7 or SLK in CCA lines abrogated tumor organoid formation and reduced orthotopic tumor growth. To translate the target to patients, we identified tivozanib as a potent SLK inhibitor. Tivozanib treatment reduced tumor organoid formation in vitro and induced tumor regression in vivo in patient derived xenografts (n=2). Together, these findings reveal a novel cytosolic XPO7:SLK signaling axis that is targetable in CCA patients and we have already documented early responses with our accruing Phase I/II trial (NCT 04645160). It is however clear that single agents will not result in cures for patients with solid tumors, and a better understanding of the XPO7:SLK complex (including downstream oncogenic signaling axes) will be required to formulate and implement synergistic combination therapies.

Persistent inflammation is a pathogenic determinant in many common human diseases, including rheumatoid arthritis, Crohn’s disease, multiple sclerosis, and psoriasis, while playing a key role in the development of type-2 diabetes, obesity, certain forms of cancer, and neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases. The laboratory of Dr. Blackshear has identified tristetraprolin (TTP) as a protein that acts to restrict inflammation in mice by destabilising the mRNA of pro-inflammatory cytokines such as TNF, GM-CSF, CXCL1 and CXCL2. Mice where an instability-conferring element within TTP’s own mRNA was deleted using homologous recombination were remarkably resistant to inflammatory disease. Most importantly, these mice did not exhibit any pathology, presumably because of the relatively modest over-expression of TTP that was otherwise subject to normal regulation.  

However, studies of TTP’s biochemical and molecular activities have been hampered by the existence of three other members of the same protein family in the mouse.  Each of these proteins exhibits similar biochemical activities in cell transfection experiments and in cell-free assays, but knockout mice of each have led to dramatically different phenotypes, involving early development, hematopoiesis, and placental function rather than inflammation.  For this reason, we will use the fruit-fly Drosophila melanogaster, which expresses only a single TTP family member, known as TIS11. Using genetics, biochemistry, transcriptomics, and proteomics we will explore the role of TIS11 and extrapolate findings to experiments in mammalian systems at NIEHS.

Sympathetic neurons have a wide range of physiological functions and their hypoactivity contributes to obesity and diabetes, among other syndromes. Sympathomimemic drugs rescue this deficiency but this drug class, mostly composed of brain-penetrant amphetamines and adrenergic agonist, is both cardiotoxic and highly controlled. Our recent publication puts forward new class of drugs named Sympathofacilitators that do not enter the brain and have an anti-obesity and cardio-neutral effect in vivo. The first in-class was published in Mahu I, Domingos, et al. Cell Metabolism 2020; Figure 3C of this paper demonstrated a neuro-facilitatory effect, rather than neuro-excitatory one.

This new class is in need of novel chemical entities which can be screened in vitro on cultured iPSC-derived sympathetic neurons. The screen would be based on fluorescent readouts of calcium activity reporter, screening for a facilitation of responses to acetylcholine (similar to Figure 3C of Mahu I, et al).

The prospect of identifying natural compounds that have a Sympathofacilitatory effect is tangible when performed in collaboration with the laboratory of Barry O'Keefe. The student will learn how to grow and scale-up iPSC-derived sympathetic neurons in the Domingos lab, and optimize an in vitro assay based on Figure 3C. The student will then transfer this knowledge to the lab of Barry O'Keefe where the screen will be performed using a fluorescent plate reader, robotic liquid handling, and a library of natural compounds.

We are interested in understanding the clonality of drug resistance in cancer (primarily in a haematological cancer called Multiple Myeloma (MM)). To achieve our goals, we have developed state of the art long-read single-cell sequencing approaches (termed scCOLOR-seq) that allow us to measure single clones within patient samples. This method allows for the simultaneous measurement of gene expression, exon mutations, exon SNPs and translocations. We apply this technology and develop cutting edge computational analysis solutions to understand the relationship between clonality and drug resistance in oncology. Furthermore, our lab is also working as part of the Human Cell Atlas (HCA) project and we have several international collaborations with immunologists, cancer biologists to support our work.

The aim of this project is to develop computational analysis strategies aimed at better defining specific MM clones within patients that are resistant to first line therapeutics. The work will involve combining long-read (Oxford Nanopore Technology) multi-modal datasets and performing machine learning approaches to better define high risk patients. This work is important to better understand drug resistance mechanisms in MM and identify patients that may respond less well to therapy.