New PhD Projects for IICD

We are looking for the best and the brightest researchers to join our research community. We're a world-leading centre for Infection, Immunity & Cardiovascular Disease research. Our pioneering discoveries help fight disease, and have an impact on clinical medicine research.

We are offering the following diverse, cutting edge PhD research projects starting in October 2016.

Defining the cellular signals required for blood vessel remodelling & vascular smooth muscle recruitment in zebrafish: A novel model for pulmonary arterial hypertension?

Project Details:

Pulmonary arterial hypertension (PAH) is a fatal disease characterised by abnormally high blood pressure in the pulmonary arteries which supply deoxygenated blood to the lungs. During PAH, the walls of pulmonary arteries become stiff and thickened and the blood vessels may become occluded. This makes it increasingly difficult for the heart to pump blood through these arteries and results in weakening of the heart muscle which can ultimately result in heart failure. Dysfunction of endothelial cells, which line the inner surface of blood vessels and pulmonary artery EC apoptosis play a central role in disease pathogenesis. Subsequent proliferation and migration of vascular smooth muscle cells (VSMCs), and recruitment of circulating cells drives pulmonary vascular remodelling. Current treatment options are limited and non-curative. An advantage of the zebrafish is its utility for identification of novel drugs via targeted chemical screens. While zebrafish do not possess a pulmonary circulation, they have gills which are similar in structure and function to lungs. Mutations in the BMP receptor BMPR2 cause PAH via apoptosis of pulmonary arterial ECs and increased VSMC proliferation. Zebrafish embryos exhibit high levels of BMP activity in the developing gill (aortic arch, AA) vessels. How BMP and other physiological conditions including hypoxia regulate gill vessel formation, remodelling and VSMC recruitment is unknown. Using live lightsheet microscopy of blood vessel formation in zebrafish embryos, this project will determine the role of cell signalling pathways known to play a role in PAH pathogenesis, in formation, remodelling and VSMC recruitment to AA vessels. Importantly, this project will establish if zebrafish can be employed to reliably screen for drugs against PAH and in functional studies to model the effect of human genomic variants identified from PAH patients, on EC/VSMC physiology in vivo.

Click here for further details.

Live Imaging of Leukocytes After Hif-a Manipulation in Tuberculosis

Project Details:

We study factors involved in host-pathogen interactions, with particular reference to tuberculosis (TB). TB kills 1.5 million people annually, and drug resistant TB is a major global threat. To investigate the complex cellular interactions involved, our model of choice is the zebrafish embryo infected with Mycobacterium marinum (Mm, fish tuberculosis, which accurately recapitulates many features of the human disease). Zebrafish embryos have an innate immune response comparable to our own (with functional macrophages and neutrophils), and are transparent, allowing detailed spatial and temporal analysis of leukocyte behaviour during infection. They are genetically tractable, and fluorescent reporter lines allow High-quality targeted imaging.
We are specifically interested in hypoxia inducible factors (Hifs), a family of transcription factors stabilised by hypoxia. Upregulating Hif-1a leads to increased generation of nitric oxide (NO, a potent antimicrobial) and a consequent decrease in infection burden (Elks et al., 2013 http://goo.gl/CxdYld), whilst the closely related Hif-2a has the opposite effect on NO and infection burden, through currently uncharacterised mechanisms. Hif-a modulation therefore represents an exciting host-based therapeutic opportunity against TB, possibly circumventing antibiotic resistance. However the effects of Hif-a’s on individual leukocyte responses during infection are poorly understood.
The aim of this project is to use the genetic and imaging advantages of the zebrafish to address the hypothesis that a balance between Hif-1a and Hif-2a can determine leukocyte bactericidal responses (and hence the outcome of infection) by regulating NO production. Novel stable transgenic zebrafish lines of leukocyte specific (macrophage or neutrophil promoter driven) Hif-a variants (dominant active/negative Hif-1a/-2a) will be generated. Using confocal fluorescence microscopy, the interactions and functional responses of different leukocyte populations during Mm infection will be imaged, initially in existing macrophage and neutrophil lines, and then in Hif-a lines once generated. Results from the zebrafish model will inform experiments in human cells (neutrophils and macrophages) in the latter stages of the project, using hypoxia or pharmacological agents to modulate HIF expression.
This work will take place in a young and vibrant research group (http://elkslab.weebly.com/) and the candidate will be well trained in a combination of cutting-edge molecular biology and microscopy techniques.

Click here for further details.

Do Neutrophil Microvesicles Play a Role in Lung Inflammation?

Project Details:

According to the World Health Organisation (WHO), more than 3 million people died fromchronic obstructive pulmonary disease (COPD) in 2012 and there are still few effective therapies. The underlying cause of COPD is an influx of inflammatory cells, predominantly neutrophils. Once activated, neutrophils can release microvesicles, small (0.1 – 1 µm) membrane-derived sacs that contain cytokines and genetic material that can be delivered to recipient cells. We have previously found that neutrophil microvesicles are internalised by endothelial cells and can influence gene expression and deliver miRNA. We hypothesise that neutrophil microvesicles are released in response to infection and exacerbate lung inflammation through activation of lung epithelial and microvascular endothelial cells.

The focus of this project is to determine whether neutrophil microvesicles induce inflammatory gene expression and functional changes in lung epithelial and microvascular endothelial cells. In addition the delivery of miRNA from microvesicles to lung cells will be investigated.

Click here for further details.

In Silico Modelling of Zebrafish Neurovascular Development

Project Details:

Lightsheet imaging provides unrivalled imaging of cell behaviour and organ patterning during zebrafish development. However, there are currently no established methods to quantify parameters that characterise the vascular anatomy, compare images between individual embryos, or compare mutant or drug-treated embryos with controls. This deficiency limits the ability to extract important biological data from lightsheet imaging datasets. This project aims to overcome these limitations by developing and evaluating an optimised image analysis workflow for quantifying neurovascular development in individual zebrafish and across populations.

Click here for further details.

Each of these IICD projects will be based within the the Faculty of Medicine, Dentistry & Health's Graduate School and be part of our University wide Doctoral Academy. The University of Sheffield as a whole combines research excellence, links with industry and a supportive research environment that will prepare you for your future career.

Please apply before 10 June 2016.