Current PhD Fellows
Supervisors : Dr Carola - Bibiane Schoenlieb Department of Applied Mathematics and Theoretical Physics & Dr Stefanie Reichelt - Cancer Research UK Cambridge Institute
Mathematical Image Analysis for Cancer Research Applications
Research in biomedical sciences is increasingly relying on digital images. At the same time, technical equipment for data acquisition and storage media are developing rapidly, raising an urgent need for suitable image enhancement and processing techniques.
In mathematical imaging a vast variety of different models and methods exists to track cells with fluorescence markers. Fluorescence imaging has the advantage of excellent signal to noise ratio, which allows for simple tracking algorithms to be applied. The disadvantage of fluorescence imaging methods is the adverse effect of fluorescent illumination on especially mammalian cells during mitosis. Cells often are arrested in mitosis when light levels are too high.
One specific problem, which has wide applications, is the development of tools for automatic mitosis detection and tracking. This is particularly important for different types of cancer cells when using phase contrast microscopy. Phase contrast is the most widely-used contrast method in light microscopy. Every tissue culture microscope is equipped with phase contrast. Time-lapse observations of cell divisions are a measurement to determine the percentage of cells undergoing mitosis (mitotic index analysis). The mitotic index is an important prognostic factor predicting both overall survival and response to chemotherapy in most types of cancer. Durations of the cell cycle and mitosis vary in different cell types. An elevated mitotic index indicates more cells are dividing, and thus is one of the key measurements in cancer drug development studies.
Other projects will comprise the analysis of extracellular matrix re-organisation in cancer tissue, i.e. quantification as well as segmentation of collagen structures, and signal to noise ratio stochastic modelling including denoising of fluorescence microscopy images.
The function and survival of compartmentalised eukaryotic cells relies on efficient and specific exchange of proteins and lipids between different membrane-bound organelles. This is achieved through a process of vesicular transport; macromolecules are packaged into membrane-bound vesicles, which bud from the donor compartment and are transported to, and subsequently fuse with, the acceptor compartment. Adaptor protein complex 4 (AP-4) is one of five closely related AP complexes, which play central roles in this process. Broadly speaking, AP complexes direct the selection and incorporation of cargo into transport vesicles, and also serve as binding platforms for other vesicle coat proteins.
The general function of AP-4 has not yet been established, but it is implicated in trans-Golgi network to endosome transport. Mutations in AP-4 are known to cause severe intellectual disability and hereditary spastic paraplegia. Our long-term goal is to understand the molecular mechanisms that underlie this pathology.
In this project we aim to study the role of AP-4 in membrane trafficking, particularly in neurons. Currently AP-4 research is hindered by a lack of identified AP-4 cargo proteins. Therefore, a key goal of our project is to identify novel candidates for both ubiquitous and neuron-specific AP-4 cargo proteins. The subsequent characterization of candidates will involve a number of biochemical and cell biology techniques, making use of a variety of cell systems, including patient cells. Hopefully, the identification of bona fide AP-4 cargo proteins will then enable us to develop a functional assay for AP-4 with which we can study the function and regulation of AP-4-mediated trafficking. Other projects will include the investigation of candidate AP-4 cargo proteins previously identified in our lab and of the role of the accessory protein tepsin, which we predict to be a core component of the AP-4 coat.
Supervisor: Professor Fiona Gilbert - Department of Radiology
Development of novel magnetic resonance imaging techniques to measure hypoxia in breast cancer
Tumour hypoxia is an important prognostic factor in oncology, linked to therapy failure and poor patient outcomes. There is growing interest in non-invasive methods to monitor the oxygenation status of tumours using magnetic resonance imaging (MRI) methods.
The purpose of this project is to develop and optimise functional MRI techniques to detect blood and tissue oxygenation level-dependent contrast in healthy human breast parenchyma and in breast cancer patients. Techniques to measure tissue hypoxia in its native state and to measure the dynamic response to hyperoxic and hypercarbic stimuli will be investigated. Over the course of my PhD, I will explore different acquisition strategies, including pulse sequence development and stimulus optimisation, as well as quantitative statistical image analysis techniques to characterise tumour hypoxia, with the aim of making these methods more widely applicable in clinical breast cancer care. More precise measures of oxygen levels in vivo would allow better selection of the most appropriate population of patients that would benefit from novel anti-hypoxia directed therapies.
Supervisor: Manj Sandhu
Epidemiology of Noncommunicable disease in sub-Saharan Africa and the translation of research into health policy
The rapidly increasing burden of non-communicable diseases (NCDs) burden in sub-Saharan Africa (SSA) poses an enormous challenge to the region. A key barrier to the development and implementation of appropriate public health policy and intervention programmes is the lack of high quality data. Context-specific high quality studies on NCDs and their risk factors in SSA are therefore imperative to provide a framework for evaluation and implementation of prevention and management strategies, and health policy in SSA.
The first phase of my research aims to assess the burden and aetiology of NCDs and their risk factors, in particular diabetes and its complications. For this, I will use data from population based epidemiological studies in Durban, South Africa and Entebbe, Uganda.
Secondly, I will conduct applied research into the prevention and control of NCDs in these countries focusing on the issues of self-management and adherence associated with chronic disease management in these settings. Finally, I aim to examine the policy implications of this research and translation into policy.
Current PhD/ACT Clinical Fellows
Acute kidney injury is an important pathology complicating multiple diseases and affecting nearly a fifth of all inpatients. While there are many potential causes, the process is mediated by a renal inflammatory state causing cell death and ultimately kidney failure. Certain immune cells play a critical role in initiating and potentiating this inflammation by producing pro-inflammatory molecules, notably IL-17 and IL-22. Th17 cells are the primary source of these molecules, however increasing evidence is mounting that a new class of immune cells, innate lymphoid cells, may also play a role.
Innate lymphoid cells have been extensively characterised in the gut, lung, skin and blood. My work will seek to identify these cells within the human kidney and elucidate their role in renal inflammation.
A forward genetic screen to identify genes required for silencing HIV
The remarkable success of Highly Active Anti-Retroviral Treatment (HAART) has transformed the life expectancy of patients with HIV. Whereas infection with this virus was previously fatal, the disease can now be controlled but requires lifelong treatment with HAART. The remaining challenge is the reservoir of latent provirus which integrates into the genome of non-dividing T-cells and is insensitive to anti-viral treatment. The maintenance of this latent virus pool is complex and only partially understood.
The aims of my project are to identify and characterise novel host cell transcriptional repressors which are involved in silencing HIV. To do this I will use a forward genetic screen in haploid cells to identify HIV silencing complexes and then perform a biochemical analysis to determine how these complexes work. A detailed understanding of the cellular processes involved in the initiation of HIV latency has the potential to lead to improved treatments against the virus, as elimination of the latent reservoir of HIV could theoretically cure this devastating disease.
Industry-linked PhD Fellows
Supervisors – Dr Tim Raine, Prof Arthur Kaser - Department of Medicine, Dr Mat Robinson - MedImmune
My PhD is funded by a MedImmune and the Cambridge Biomedical Research Centre.
My research interests lies in understanding the transcriptional and epigenetic profiles of individual cell populations relevant to IBD pathogenesis.
Supervisors: Prof Fiona Gribble - Institute of Metabolic Science, Dr Frank Reimann, Dr Peter Ravn and Dr David Hornigold - MedImmune
Use of antibodies to the GLP1-R and GIP-R to investigate the distribution and function of the receptors in cardiovascular and metabolic physiology
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are incretin hormones that stimulate insulin secretion in response to glucose, particularly on oral administration. Despite GLP-1 receptor agonists being widely prescribed for type 2 diabetes and being in late clinical trials for treatment of obesity, considerable uncertainty has remained about important aspects of the distribution of GLP-1 receptors and their function in cardiovascular and metabolic physiology. The biological role of GIP and the interaction with GIPr have been extensively studied, but uncertainty remains about the predicted therapeutic effects of modulating GIP action to regulate plasma glucose and fat deposition in adipocytes.
The purpose of this project is firstly to affinity mature and characterise antagonistic GLP1R antibodies, generated at MedImmune. An antagonistic human antibody, Gipg013, to the human GIPR is available for use in studies. Antagonistic GLP1R antibodies and GIPR antibodies will allow the chronic suppression of GLP-1 and GIP activity. The antibodies will be used to investigate the functions of GLP-1 and GIP, with focus on cardiovascular and metabolic physiology.
Research details to follow