Biomedical Science PhD project opportunities

Find out more about self-funded PhD projects in areas of biomedical science.

We already have supervisors active and engaged in the research topic in our School of Life Sciences.

Cardiovascular

Development of novel macrophage high through-put cell-based phenotypic assay for drug screening

Research Group

Biomedical Research Group

Proposed supervisory team

Dr Grisha Pirianov

Prof Selim Cellek

Theme

Cardiovascular, Translational Biomedicine

Summary of the research project

Background: Macrophages play a critical role in homeostasis and diseases. They can change their phenotype to perform differential activities in different phases of inflammatory response.

Polarized macrophages are broadly classified into two groups:

  • classical activated M1 (pro-inflammatory)
  • alternative activated M2 (anti-inflammatory).

It has been demonstrated that M1/M2 switch plays critical role in inflammation which is dependent on various factors such as bioavailability of different subsets of monocytes and macrophages, sequential monocytes recruitment into the tissue in the process of inflammation or response to different conditions. Furthermore, the misbalance of M1/M2 switch can lead to chronic inflammatory diseases. Undoubtedly the generation of novel anti-inflammatory drugs regulating M1/M2 switch is an important step for pharmacological intervention of chronic inflammatory-based diseases. Unfortunately, the current drug screening strategies are not based on macrophage polarization. The development of a phenotypic macrophage high-throughput assay will provide a platform for screening of pro or anti-inflammatory properties of the candidate molecule (preclinical drug validation) or FDA approved drugs library and selected compound libraries with known anti-inflammatory activity (clinical drug validation).

Main goal and objectives: The main goal of the study is to develop and validate a novel phenotypic macrophage high-throughput cell-based assay for anti-inflammatory drug screening activity. The two main objectives are:

  • to develop a cell-based M0/M1/M2 phenotypic screen
  • to investigate the effect of novel small molecules (TLR4 antagonists) and selected compound libraries with known anti-inflammatory activity on M0/M1/M2 screen.

Methodology: Cell culture and cell-based essays, western blotting, ELISA approaches.

Collaborations: This project is based on academic and industrial collaborations with Reading University and Innaxon, UK respectively.

Outcomes: Results from this project will evaluate the potential of the phenotypic macrophage high-throughput assay for drug screening as well as provide important information about the effect of the candidate molecules on macrophage polarisation and will contribute to their preclinical/clinical validation. This will represent a finding of great public and commercial impact as currently there are no macrophage cell-based phenotypic assays for drug screening. The proposed project will have a commercial value and we plan to secure protection of the arising intellectual property.

Where you'll study

Cambridge

Funding

This project is self-funded.

Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website as they become available.

Next steps

If you wish to be considered for this project, you will need to apply for our Biomedical Science PhD. In the section of the application form entitled 'Outline research proposal', please quote the above title and include a research proposal.

Investigating the potential of novel mimetic molecules (Toll-like receptor 4 antagonists) to modulate the microphage polarisation

Research Group

Biomedical Research Group

Proposed supervisory team

Dr Grisha Pirianov

Dr Nicholas Pugh

Theme

Cardiovascular, Translational Biomedicine

Summary of the research project

Background: Toll-like receptors (TLRs) serve as pattern recognition receptors within the immune system. Among these receptors TLR4 is activated in response to bacteria and other non-bacterial ligands such as heat shock proteins, small fragments of hyaluronan, and even oxidised low density lipoproteins (oxLDL) in immunocompetent cells. TLR4 expression has been described in monocytes and microphages. TLR4 and different macrophage subsets have been shown to be implicated in inflammatory related diseases suggesting that understanding mechanisms of modulation of TLR4 signalling may be of great importance for pharmacological treatment of atherosclerosis.

Although existing TLR4 antagonists have been discontinued from clinical trials due to lack of efficacy, recently, a novel compound family designed as small molecule TLR4 antagonists have been developed to specifically modulate TLR4 signalling. We have recently shown that one of these molecules (AXO-102) negatively regulated in vivo and in vitro TLR4 signalling in vasculature and inhibited early rupture and incidence of aneurysms formation.

Main goal: This project will investigate the potential of IAXO-102 and other mimetic molecules to modulate the macrophage polarisation (formation of specific subsets) in response to sterile inflammation.

There are three main objectives:

  1. To investigate the effects of TLR4 sterile ligand agonists (small fragments of hyaluronan and oxLDL) on TLR4 expression and activation on the macrophage polarisation.
  2. To examine the effects of TLR4 sterile ligand agonists to stimulate production of TLR4-dependent pro-inflammatory proteins on the macrophage polarisation.
  3. To investigate the potential of novel molecule TLR4 antagonists to modulate TLR4 signalling in relation to microphage polarisation.

Methodology: Cell culture and cell-based essays, western blotting, ELISA and antibody array approaches.

Collaborations: This project is based on academic and industrial collaborations with Reading University and Innaxon, UK respectively.

Outcomes: The results from this study will validate the potential of novel TLR4 antagonists as candidates for pre-clinical studies for pharmacological intervention of atherosclerosis.

Where you'll study

Cambridge

Funding

This project is self-funded.

Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website as they become available.

Next steps

If you wish to be considered for this project, you will need to apply for our Biomedical Science PhD. In the section of the application form entitled 'Outline research proposal', please quote the above title and include a research proposal.

Novel regulation of platelet-endothelial crosstalk in settings of vascular disease

Research Group

Biomedical Research Group

Proposed supervisory team

Dr Nicholas Pugh

Dr Havovi Chichger

Theme

Cardiovascular, Translational Biomedicine

Summary of the research project

Various disease states damage the function of blood vessels, including diabetes, atherosclerosis and bacterial infections. The level of injury is dependent on the physiological insult and vascular bed. Maintenance of an intact endothelium is vital to prevent infiltration of immune cells or fluids. Platelets interact with the endothelium under conditions where the vessel wall is damaged, resulting in adhesion and aggregation of platelets to form a clot and arrest bleeding. The cell signalling mechanisms which regulate endothelial integrity and platelet aggregation are currently studied however the precise molecular mechanisms resulting in breakdown of barrier integrity and subsequent platelet interactions is not wholly understood.

The project will investigate novel mechanisms which regulate the cross-talk between the platelets and endothelium in settings of vascular disease. In particular, the research will focus on systemic factors associated with diet and the microenvironment at sites of vascular injury.

Research methods will include cell culture and platelet aggregation studies, as well as biochemical assays such as Western blotting and PCR analysis.

Where you'll study

Cambridge

Funding

This project is self-funded.

Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website as they become available.

Next steps

If you wish to be considered for this project, you will need to apply for our Biomedical Science PhD. In the section of the application form entitled 'Outline research proposal', please quote the above title and include a research proposal.

Regulation of mineralisation in atherosclerotic lesions

Research Group

Biomedical Research Group

Proposed supervisory team

Dr Joseph Bird

Dr Grisha Pirianov

Theme

Cardiovascular

Summary of the research project

Atherosclerosis is a disease of the arteries which develops from localised inflammation in the artery wall. This occurs concomitant with a build-up of fatty deposits, dead cells and mineral deposits at these sites. Everyone develops some degree of atherosclerosis and overtime, depending on genetic and lifestyle factors such as a fatty diet and exercise, these lesions can become weak and rupture. A ruptured lesion will cause localised blood clotting. These clots can break away from the vessel wall and migrate with the blood flow to smaller arteries where blockage can occur, causing vascular diseases such as heart attacks, stroke and peripheral limb ischaemia. Currently, 420 people a day in the UK will die from cardiovascular diseases, with 7 million people living with the consequences of the disease.

Atherosclerotic inflammation and mineralisation are considered to be the end points of the development of atherosclerotic lesions. Thus, these two processes have the potential to be used as markers of atherosclerotic lesions likely to rupture, and may help in indicating patients at risk of developing the clinical consequences (heart attack and stroke). The mineral deposits in atherosclerotic lesions are formed from calcium hydroxyapatite deposition in a manner similar to bone formation. Bone material is produced by osteoblasts and osteoblast-like cells have been found in atherosclerotic lesions. These cells are thought to arise by the transformation of the resident vascular smooth muscle cells to an osteoblast-like phenotype. However, the biological processes regulating the cell transformation and subsequent mineralisation remain unclear.

Main goal

This project will investigate novel mechanisms by which mineralisation occurs during the development of atherosclerosis and in particular, the role that localised inflammation plays in this process. The main objectives are to:

  1. Investigate the factors which induce vascular smooth muscle cells to adopt an osteoblast-like phenotype.
  2. Investigate the signalling pathways which regulate the change in phenotype.

Research methods will include cell culture studies and biochemical assays including Western blotting, ELISA and qPCR analysis.

Outcomes

The expected outcome is an improved understanding of the processes by which vascular smooth muscle cells are induced to adopt an osteoblast-like phenotype and in particular, the signalling mechanisms involved.

Where you'll study

Cambridge

Funding

This project is self-funded.

Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website as they become available.

Next steps

If you wish to be considered for this project, you will need to apply for our Biomedical Science PhD. In the section of the application form entitled 'Outline research proposal', please quote the above title and include a research proposal.

Regulation of the tissue degradation in osteoarthritis

Research Group

Biomedical Research Group

Proposed supervisory team

Dr Joseph Bird

Dr Felicity Savage

Theme

Cardiovascular, Connective tissue, Translational Biomedicine

Summary of the research project

Osteoarthritis (OA) is the most frequent of the arthritides with an incidence of 1 in 10 in those over 60 years of age. The disease is typified by the degradation and chronic loss of the cartilage that covers the ends of the bones. Currently, there is no cure for osteoarthritis beyond pain relief and joint replacement. Hyaline cartilage functions by providing both low friction surfaces in the joint and impact absorbance during locomotion. Chondrocytes are the principal cell type of hyaline cartilage and produce the extracellular matrix (ECM) which, provides the tissue with the capacity to resist mechanical load. The progression of the disease is characterised by an irreversible loss of the tissue and by chondrocyte cell death.

Osteoarthritis is linked most frequently to the “wear and tear” processes accompanying a lifetime of joint use and episodic joint inflammation. This project will investigate novel mechanisms involved in cartilage degradation and in particular, the intracellular signalling pathways, which regulate the degradative processes.

Main goal

This project will investigate the mechanisms by which cartilage is induced to degrade, using cell culture models. The main objectives are to:

  1. Investigate the signalling pathways involved in regulating cartilage degradation and chondrocyte homeostasis
  2. Investigate the regulation of proteases involved in cartilage degradation by these signalling pathways.

Research methods will include tissue and cell culture studies, and biochemical assays including Western blotting, ELISA, zymography and qPCR analysis.

Outcomes

The expected outcome is an improved understanding of the signalling mechanisms involved in cartilage degradation, which may identify future therapeutic targets for reducing the degradation of cartilage in the arthritides.

Where you'll study

Cambridge

Funding

This project is self-funded.

Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website as they become available.

Next steps

If you wish to be considered for this project, you will need to apply for our Biomedical Science PhD. In the section of the application form entitled 'Outline research proposal', please quote the above title and include a research proposal.

Understanding how p18/LAMTOR1 maintains the pulmonary endothelium – a potential therapeutic target for chronic respiratory diseases

Research Group

Biomedical Research Group

Proposed supervisory team

Dr Havovi Chichger

Theme

Cardiovascular

Summary of the research project

Around 12 million people in the UK are diagnosed with respiratory diseases such as obstructive pulmonary disease, respiratory distress syndrome and pulmonary hypertension. Patients with respiratory disease suffer from a range of pathologies, such as hypoxia and pulmonary edema, associated with cardiovascular complications and increased mortality. One of the hallmarks of this group of diseases is disruption of the pulmonary microvasculature however despite significant efforts in the field, there is still no effective treatment to reduce this injury in patients with respiratory disease.

In respiratory diseases, there is an increase in oxidative stress and actin remodelling in the pulmonary endothelium, resulting in breakdown of the vasculature. We have identified a novel protein in the pulmonary endothelium, p18/LAMTOR1, which is downregulated in respiratory disease models. Proposed studies are needed to understand the mechanism through which this novel protein maintains a healthy endothelium. The research question for this PhD project is therefore: does p18/LAMTOR1 regulate oxidative stress and actin remodelling in the pulmonary endothelium? Proposed studies will address a new area of research which will develop our understanding of p18/LAMTOR1 in the endothelium and provide data to support a potential therapeutic target to improve microvascular function in patients with respiratory diseases.

Methodology

Research will be performed using a range of in vitro techniques with healthy pulmonary arterial endothelial cells (HPAEC) to measure the role of p18/LAMTOR1 in regulating oxidative stress, actin remodeling and barrier function in the pulmonary endothelium.

Expected outcomes

Findings are anticipated to establish p18/LAMTOR1 as a key protein which regulates the pulmonary endothelium. The PhD will give insight into the mechanism through which p18/LAMTOR1 maintains the endothelium and expand our understanding of the novel role of the protein in the lung. Studies are anticipated to implicate p18/LAMTOR1 as a therapeutic target in maintaining a healthy endothelium.

Where you'll study

Cambridge

Funding

This project is self-funded.

Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website as they become available.

Next steps

If you wish to be considered for this project, you will need to apply for our Biomedical Science PhD. In the section of the application form entitled 'Outline research proposal', please quote the above title and include a research proposal.

Understanding how the bitter taste receptor, T2R38, regulates the intestinal epithelium - a study from microbiota to the intestinal epithelium

Research Group

Biomedical Research Group

Proposed supervisory team

Dr Havovi Chichger

Theme

Cardiovascular

Summary of the research project

Increased gastric permeability is associated with metabolic diseases such as diabetes and obesity. Maintenance of a healthy, intact intestinal epithelial barrier is vital to prevent inflammation and septicemia seen in these diseases. The intact barrier is preserved through the formation of junctional complexes between intestinal epithelial cells. We have recently shown that the activation of sweet taste receptors, by sweeteners, increases leak across the intestinal epithelium by breakdown of these junctional complexes. We have further demonstrated that sweeteners increase the ability of model bacteria, in the gut microbiota, to damage intestinal epithelial cells. In contrast, far less is understood about bitter taste sensing in the intestinal epithelium, despite the high number of bitter taste receptors in the G-protein coupled receptor family. Interestingly, increased expression of bitter taste receptor T2R38 observed in the specialized gastrointestinal tract cells of obese patients. Preliminary studies from the laboratory, using intestinal epithelial cells, show that stimulation of T2R38, by phenylthiourea, increases breakdown of tight junctions maintaining the epithelial barrier and increased leak. The research project will therefore address the hypothesis that bitter taste sensing regulates the intestinal epithelium through acting on microbiota and intestinal epithelial cells. By understanding the mechanisms regulating these processes, we aim to develop novel therapeutic targets to improve intestinal epithelial barrier function and therefore reduce inflammation and septicaemia in patients with metabolic disease.

Methodology

To test this hypothesis, studies will be performed using a combination of microbiology and cell culture studies using two model gut bacteria (E.coli NCT, E. faecalis) and a transformed cell model of the intestinal epithelium (Caco-2 cells). These two models, currently used in the laboratory, will be studied as a co-culture using bitter taste agonists to study the functional response. Key outcomes are changes in metabolism or pathogenic effect of bacteria on the epithelium and breakdown of the intestinal epithelial barrier.

Expected outcomes

Findings from the project will demonstrate the molecular mechanisms through which activation of bitter taste receptors can regulate function of the intestinal epithelium. This investigation is anticipated to demonstrate that taste receptors represent novel therapeutic targets in the treatment of inflammation and septicaemia in patients with metabolic diseases.

Where you'll study

Cambridge

Funding

This project is self-funded.

Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website as they become available.

Next steps

If you wish to be considered for this project, you will need to apply for our Biomedical Science PhD. In the section of the application form entitled 'Outline research proposal', please quote the above title and include a research proposal.

Genetics

The role of circadian genomics in epilepsy and pharmaco-resistance

Research Group

Biomedical Research Group

Proposed supervisory team

Dr Krithika Sundararaman

Dr Francesca Panin

Dr Arjune Sen (University of Oxford)

Theme

Genetics, Bioinformatics

Summary of the research project

This project aims to explore one of the promising areas of epilepsy genetics: the role of clock genes in development of seizures and its contribution to pharmaco-resistance in epilepsy. Epilepsy is a distressingly common neurological disorder characterised by aberrant bursts of electrical activity in the brain, or seizures, leading to various symptoms, including altered consciousness, unusual behaviours, and uncontrolled movements. Literature shows an apparent link between both seizure frequency and type of epilepsy to the circadian cycle - the internal process that regulates our daily physical, mental and behavioural changes. Circadian rhythm is the result of the expression of a set of clock genes. The interaction, regulation and expression of clock genes is vital for the homeostasis and tuning of many important functions, including the sleep/wake cycle and day/night activity patterns. Recent studies demonstrate that clock genes are altered in neurodevelopmental disorders and identified common associations between seizures and sleep-wake states. The frequency of seizures can be associated to a specific time of the day, for example being highest in the middle of the wake period, thus suggesting an important role of ‘time-of-day’ factors in the expression of the seizures. It can, therefore, be hypothesised that alterations of specific clock genes link to the onset of seizures and to the type of epilepsy. Exploration of whether circadian rhythms control distinct mechanisms of neuronal hyperexcitability might offer new insights into seizure genesis and lead to new therapeutic strategies. One further application will also be to identify specific associations between disrupted clock genes/mechanisms and pharmaco-resistance in epilepsy, which is failure to achieve seizure control with anticonvulsant medications. Specific associations between altered clock genes/mechanisms and epilepsy will serve as biomarkers of vulnerability to epilepsy and pharmaco-resistance and will facilitate the development of personalized treatments in the longer run.

Methodology

To address the aims and objectives of the proposed study, data from the 100,000 genomes project, led by Genomics England, will be used. The neurology domain of the Genomics England project (GEL) comprises the whole-genome sequencing (WGS) data of thousands of people with epilepsy, including their detailed clinical information and family history. We already have access to the GEL research environment and any new projects are readily approved by the GEL research team. The whole-genome sequences of epilepsy cases will be screened for rare variants in a curated list of clock genes by utilizing different bio-informatic tools involved in next generation sequencing data analysis. The variants will further be analysed for different parameters, including their frequency in different public databases and their pathogenicity, which will be evaluated using in-silico tools. The final set of credible clock gene variants will be clinically evaluated using the available clinical information of these cases.

Expected outcomes

Better understanding how circadian mechanisms contribute to regulation of seizures would have important clinical applications including: i) diagnosing the type of epilepsy, ii) determining specific associations between the onset of seizures and alterations of genes that regulate sleep patterns iii) identifying possible causes for pharmaco-resistance.

Where you'll study

Cambridge

Funding

This project is self-funded.

Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website as they become available.

Next steps

If you wish to be considered for this project, you will need to apply for our Biomedical Science PhD. In the section of the application form entitled 'Outline research proposal', please quote the above title and include a research proposal.