Prof Endre Kiss-Toth, Prof D Coca, Dr H Wilson
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
This three and a half (3.5) year studentship is part of the Healthy Lifespan Institute at The University of Sheffield. This exciting new research initiative is dedicated to the understanding and prevention of multimorbidity, which is the presence of two or more chronic health conditions that create disability and poor quality of life in old age. We are taking a unique multidisciplinary approach that spans the biological and social sciences and strive to create new practices, policies and products across the life course that target multiple conditions and help people live longer, healthier and more independent lives.
As a student within the Healthy Lifespan Institute, you will be a valued and active member of the Institute and your work will be vital in contributing to our aims and helping to effect real change.You will be part of a wider multidisciplinary network of PhD students and will have the chance to influence and lead Institute activity, (i.e. sitting on Committees, representation at Exec, designing a programme of activities), to take part in seminars and events, and to meet leaders in the field.
Research Project:
Macrophages are involved in self-defence against pathogens and in tissue homeostasis and repair. They are important to detoxify tissues by clearing apoptotic cells and modified lipids. In response to environmental cues, macrophages are able to shift from an inflammatory to a reparative phenotype. Whilst it is known that macrophage function declines with old age, little systematic work has been published that directly investigates the molecular mechanisms of age-related changes in human primary macrophages.
This project combines complementary interests in macrophage biology and their role in immuno-metabolic diseases, machine learning, and modelling transcriptional dynamics of activated macrophages. We will study monocyte derived macrophage (MDM) responses from healthy young adults vs aged human subjects.
A systems biology approach, combining mathematical modelling and computational biology with experimental data will be used to characterise the dynamic transcriptional landscape of macrophage activation. Pathway analysis tools, discrete-logic modelling and optimization will be used to infer from data contextualised Prior Knowledge Network (PKN) models of macrophage activation and lipid processing to predict missing expression values, analyse network stability or to simulate transitions between macrophage activation states in response to perturbations.
Project Aims and Objectives:
We hypothesise that macrophages isolated from aged (>58 years) individuals, compared to young individuals (20-25 years) have impaired responsiveness to stimuli and are unable to shift effectively from an anti-inflammatory to a pro-inflammatory (and vica versa) state due to dysregulated execution of transcriptional programmes driving macrophage polarisation and function. Macrophages from aged compared to young subjects may also have an attenuated ability to uptake and process lipoproteins, a critical risk factor in the development of atherosclerosis.
The project has two major Aims:
To investigate experimentally the dynamics of macrophage responses isolated from young vs. aged human volunteers, in response to stimuli relevant to the development of Cardiovascular Disease (Y1-2)
To develop computational models that predict critical genes that underpin physiological and dysregulated macrophage responses (Y2-4)
Supervision and Mentorship:
To reflect the complex challenges of addressing multimorbidity the Healthy Lifespan Institute seeks to create highly interdisciplinary collaborations across the different faculties of the University of Sheffield and with external partners. This studentship will be jointly supervised by senior academics Prof. Endre Kiss-Toth (Department of Inflection, Immunity and Cardiovascular Disease, Faculty of Medicine, Dentistry & Health), Prof. Daniel Coca (Automated Control Systems Engineering, Faculty of Engineering) & Dr Heather Wilson (Department of Inflection, Immunity and Cardiovascular Disease, Faculty of Medicine, Dentistry & Health). External mentoring will be led by Prof. Francesco Falciani (Institute of Integrative Biology at the University of Liverpool).
Supervisors: Prof. Endre Kiss-Toth (Department of Inflection, Immunity and Cardiovascular Disease, Faculty of Medicine, Dentistry & Health), Prof. Daniel Coca (Automated Control Systems Engineering, Faculty of Engineering) & Dr. Heather Wilson (Department of Inflection, Immunity and Cardiovascular Disease, Faculty of Medicine, Dentistry & Health).
External Mentors: Prof. Francesco Falciani (Institute of Integrative Biology at the University of Liverpool)
Funding Notes
Funding details and salary/stipend rate:
Each studentship will be supported for 3.5 years with the student expected to submit their thesis by the end of this funding period.
Students will be provided with:
A full award paying fees and maintenance at the standard Research Council rates (stipend £15,285 & fees £4,407 in 2020-21).
Research Training Support Grant of £1,500 per year
References
Entry Requirements:
Candidates must have:
Upper second class honours degree (2.1) or above in biology or biomedical sciences and significant interest in computational approaches to analysing dynamic cellular processes and complex biological problems.
Significant laboratory experience, preferably including mammalian cell culture and basic cell biology techniques.
Programming skills (R, Python), are highly desirable.
A proven track record in working as part of a team, as well as independently.
Good time-management skills.
Proposed start date: 1st October 2020
How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply
Please clearly state the title of the studentship, the prospective main supervisor and select Infection, Immunity and Cardiovascular Disease as the department.