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.
Supervisor: Prof Margaret Robinson – Cambridge Institute for Medical Research
The role of adaptor protein complex 4 in health and disease
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.
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.
‘Statistical co-analysis of high dimensional association studies’
Primary supervisor – Dr Chris Wallace
Secondary supervisor – Dr Eoin Mckinney
I work in the development of statistical methods for efficiently comparing high-dimensional association studies, typically in genomics.
This is important in extending our understanding of genetic risk to complex disease structures. Many common diseases are heterogeneous, with multiple possible causes, and many nominally distinct diseases may be caused by similar pathologies – but many historical genetic studies have been necessarily limited to simple case-control designs, which do not model this complexity. Larger datasets and more extensive characterisation of patients are allowing this problem to be addressed, and have great promise for the development of more precise medical treatments. With this promise comes many mathematical and statistical challenges which my PhD work attempts to address.
Supervisors: Prof F. Hollfelder and Dr. M. Snaith
After receiving my BSc in Interdisciplinary Sciences at ETH Zurich, I completed my MSc in October 2015 with a major in Biology and Chemistry. My master’s thesis in Prof. F. H. Arnold’s group at Caltech (Pasadena, USA) comprised the directed evolution of a tryptophan synthase beta-subunit for substrate promiscuity to enable enzymatic synthesis of a broad range of non-canonical amino acids. After a student internship at Roche, where I evaluated a novel affinity tag for mass-spectrometric analysis of cell surface proteins, I joined Prof. F. Hollfelder’s group for my PhD studies.
My project in his lab is in collaboration with MedImmune and aspires to enhance CRISPR-associated (Cas) nucleases – focussing on Cas9 and Cpf1 – for genome editing by means of directed evolution. The microfluidic droplet-based screening platform allows for a high-throughput investigation of extensive Cas nuclease libraries. This way I aim to identify mutants with improved genome editing capability that are both of biotechnological and potentially clinical interest.
Supervisors: Dr Clemence Blouet and David Baker
My current research interest lies in central mechanisms underlying the synergistic anorectic effect of combination therapies. My PhD project focuses mainly on the neuro-anatomical localization and identification of the cell groups implicated in the synergistic integration of cholecystokinin A receptor agonist and glucagon-like peptide-1 receptor agonist and the characterization of the associated intracellular mechanisms involved in the integration.
Supervisor: Dr Anthony Davenport
Petra graduated as a Medical doctor from the University of Zagreb in 2005, and completed her clinical training in Internal Medicine. She worked as a Consultant in Internal medicine, with significant involvement with the Diabetes and Endocrinology division, where she was also exposed to wide spectrum of teaching roles of undergraduates, junior doctors and GPs. She continued this theme on joining the Department of Endocrinology and Diabetes at Cambridge University Hospitals as a Clinical Fellow. She is currently a fully funded EMI/Astra Zeneca/MedImmune PhD student, undertaking research in experimental medicine studies, which will be carried out in volunteers and patients with diabetes. Her research will focus on understanding the role of the peptide hormones apelin and relaxin in human physiology, and establishing their potential as novel agents for the treatment of diabetes and heart failure.
Supervisors: Dr Thomas Hiemstra and Dr Joseph Cheriyan
Zoe graduated from the Hull-York Medical School with an MBBS and BSc (Hons) degree in Medical Science. Her research focused on the role of mouse spleen cell surface receptor SIGN-R1, homologous to the human DC-SIGN, in the pathophysiology of visceral Leishmaniasis. She subsequently completed her foundation training in the West Yorkshire Foundation School. She then continued her research as an NIHR Academic Clinical Fellow in Vascular Surgery at the Leeds General Infirmary, where she carried out a series of Clinical Research Studies before entering into higher speciality training in Vascular Surgery. She has been appointed as an EMI / GSK funded doctoral research training fellow and her work will focus on the cardiovascular effects of erythropoiesis stimulating agents (ESAs).
Supervisors: John Bradley, John Waters, and Carol Moreno Quinn
Treatment of chronic kidney disease (CKD) is currently limited because therapies are unable to prevent fibrosis, the major pathological process associated with progression. Glomerulosclerosis is the glomerular fibrosis and scarring that occurs in many forms of CKD, leading to impaired glomerular filtration. Culture of cells in three dimensions (3D) enables the modelling of disease using human cells to answer basic research questions and test possible therapeutic targets in a more relevant system, avoiding the need for animal models.
My project tests the hypothesis that 3D culture of three glomerular cell types can be used to model glomerulosclerosis and better understand disease pathogenesis and cross-talk between the glomerular cell types and identify targets to prevent/reverse fibrosis.
Supervisors: Simone Weyand and David Lowe
I am a second year PhD student in Simone Weyand’s lab in the biochemistry department with a second supervisor, David Lowe, at MedImmune. My project focuses on the high-resolution structure determination of the human Formyl Peptide Receptor 1 (FPR1), which is a G-protein coupled receptor involved in cancer and the inflammatory response. I aim to stabilise and purify the receptor in complex with a high affinity Fab fragment provided by MedImmune and determine the structure by electron cryomicroscopy (cryo-EM). A range of techniques will be used to ensure the stability and functionality of the receptor including radioligand-binding assays to check for thermostable mutants, which can be combined to produce an optimally stable receptor for structural studies.