Chemokine gradient development around lymphatic vessels during immune and inflammatory responses

Chemokine gradient development around lymphatic vessels during immune and inflammatory responses
Modelling and Analytics for Medicine and Life sciences Doctoral Training Centre: PhD Scholarship

Supervisors: Dr Bindi Brook (Mathematical Sciences), Professor Markus Owen (Mathematical Sciences)

Project description: The precisely orchestrated migration of leukocytes (white blood cells of the immune system) is a key feature of all immune and inflammatory responses, including those that occur in infectious diseases. Rapid leukocyte transport around the body is facilitated by fluid delivery in the blood and lymphatic vessels.

However, their guidance to key destinations in tissues, lymph nodes or other tissue spaces is driven by gradients in a family of small secreted proteins called chemokines. Despite major advances in understanding chemokine function, it is still unclear how chemokine gradients are formed, maintained and regulated in tissues.

In addition to molecular diffusion, chemokine binding to extra-cellular matrix (ECM) components is likely to play a key role. Interstitial fluid flow will also contribute to gradient formation, and in the case of chemokine production near blood or lymphatic vessels, the transmural movement of fluid is likely to advect chemokines further into tissues than would be possible by pure diffusion. ’Atypical’ chemokine receptors (ACKRs), a small family of molecules that scavenge and destroy extracellular chemokines are also likely to play a critical role in establishing, stabilizing and regulating chemokine gradients. The type of leukocyte migration induced depends on chemokine context, with soluble chemokine gradients directing chemotactic cell movement (migration up concentration gradients), while immobilized chemokine gradients induce integrin-dependent haptotaxis (migration up adhesion gradients).

The mechanisms that set up these gradients therefore include diffusion, advection (fluid movement), cell-mediated scavenging, and selective binding to extracellular matrix (ECM), some of which may be modified during inflammation. The aim of this project will be to develop mathematical models of chemokine gradient development during an immune or inflammatory response. The models will be developed in collaboration with immunologists based at the University of Glasgow (Profs Nibbs and Graham) [1], and a bioengineer at Imperial College London (Prof James Moore) who will be quantifying chemokine transport dynamics using a novel microfluidic platform to obtain a better understanding of chemokine transport and distribution in interstitial tissues around lymphatic vessels.

References
Immune regulation by atypical chemokine receptors. Nibbs and Graham. Nature Reviews Immunology 13:815-829, 2013.

The MAML programme: The MAML doctoral training programme focuses on innovative modelling, simulation and data analysis to study real-world problems in medicine and biology. Maintaining a healthy society creates major challenges in areas including ageing, cancer, drug resistance, chronic disease and mental health. Addressing such challenges necessitates continuing development and implementation of a raft of new mathematical approaches and their integration with experimental and clinical science. Students will apply mathematical approaches (from areas such as dynamic modelling, informatics, network theory, scientific computation and uncertainty quantification) to research projects at the forefront of biomedical and life sciences identified through well-established collaborations with both academic and industrial partners.

MAML students will be provided with an excellent training environment within the Centre for Mathematical Medicine and Biology and collaborating departments. Students will undertake tailored training, complemented by broadening, soft-skills, wet-lab (where appropriate) and student-led activities. There will also be opportunities for training and exchanges with world-leading partners.

Summary: These 3.5 year PhD scholarships start in September 2018. Successful applicants will receive a stipend (£14,553 per annum for 2017/8) for up to 3.5 years, tuition fees and a Research Training Support Grant. Fully funded studentships are available for UK applicants. EU applicants who are able to confirm that they have been resident in the UK for a minimum of 3 years prior to the start date of the programme may be eligible for a full award, and may apply for a fees-only award otherwise

Applications: Please follow the instructions at the MAML website: http://www.nottingham.ac.uk/mathematics/maml Applicants for the MAML programme should have at least a 2:1 degree in mathematics, statistics or a similarly quantitative discipline (such as physics, engineering, or computer science).

Completed applications and references should be submitted by Wednesday 28 February 2018.


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