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Cell Deformation Cytometry for Studying of the Role of Perineuronal Nets in controlling the Biomechanics of Neuronal Cells

PGR-P-856

Key facts

Type of research degree
PhD
Application deadline
Ongoing deadline
Project start date
Friday 1 October 2021
Country eligibility
International (open to all nationalities, including the UK)
Funding
Competition funded
Source of funding
Doctoral training partnership
Supervisors
Professor Stephen Evans and Dr Ralf Richter
Additional supervisors
Dr Jessica Kwok
Schools
School of Physics and Astronomy
Research groups/institutes
Molecular and Nanoscale Physics
<h2 class="heading hide-accessible">Summary</h2>

Perineuronal nets (PNNs) are hydrogel-like layers of aggregated brain extracellular matrix molecules that enwrap a subpopulation of neurones and are instrumental for the regulation of neuroplasticity. The level of PNN cross-linking, defined in part by the basic PNN components but also by PNN-binding neuronal guidance molecules, inevitably defines the mechanical characteristics of PNNs. Here, we hypothesise that the molecular assembly of PNNs stiffens neurones and, ultimately, modulates synaptic connections. <br /> The deformability of a cell is the direct result of a complex interplay between the different constituent elements at the subcellular level, coupling a wide range of mechanical responses at different length scales. The response to mechanical stress depends strongly on the forces experienced by the cell. Here, we will use cell deformability in microfluidic platforms to probe different aspects of the role of PNNs in controlling cell stiffness. Deformation traces as a function of time contain a rich source of information including maximal strain, elastic modulus, and cell relaxation times and thus provide a number of markers for understanding cell behaviour. You will develop new microfluidics and high-speed microscopy approaches to study the mechanical properties of cells and working closely with biology will apply these approaches to understanding the role of PNNs in controlling cell stiffness.

<h2 class="heading hide-accessible">Full description</h2>

<p><strong>Background.</strong>&nbsp;Cells in the central nervous system are capable of sensing the mechanical properties of their environment. Although the establishment of new synapses is critically dependent on the properties of the receiving neuronal surface, the mechanical properties of individual neurones and their surfaces remain largely unknown. How the mechanical properties on the surface of neurones affect growth cone guidance and synapse formation remains a key question.</p> <p>Perineuronal nets (PNNs) are hydrogel-like layers of aggregated brain extracellular matrix molecules that enwrap a subpopulation of neurones and are instrumental for the regulation of neuroplasticity. The level of PNN cross-linking, defined in part by the basic PNN components but also by PNN-binding neuronal guidance molecules, inevitably defines the mechanical characteristics of PNNs. Here, we hypothesise that the molecular assembly of PNNs stiffens neurones and, ultimately, modulates synaptic connections.&nbsp;</p> <p><strong>Approach.</strong>&nbsp;The deformability of a cell is the direct result of a complex interplay between the different constituent elements at the subcellular level, coupling a wide range of mechanical responses at different length scales. Changes to the structure of these components can also alter cell phenotype, which points to the critical importance of cell mechanoresponse in biology. The response to mechanical stress depends strongly on the forces experienced by the cell. Here, we will use cell deformability in both shear-dominant and inertia-dominant microfluidic flow regimes to probe different aspects of the role of PNNs in controlling cell stiffness.&nbsp;&nbsp;Deformation traces as a function of time contain a rich source of information including maximal strain, elastic modulus, and cell relaxation times and thus provide a number of markers for understanding cell behaviour.[1]</p> <p>You will&nbsp;</p> <ol> <li>Develop /improve our microfluidic platforms for studying cell deformation using high speed imaging (&amp; fluorescence microscopy).</li> <li>Determine the deformation index (DI)&nbsp;&nbsp;and elastic modulus (Y) in a previously established PNN cell model using a human embryonic kidney (HEK) cell line.&nbsp;</li> <li>Evaluate DI &amp; Y as a function of flow conditions</li> <li>Evaluate DI &amp; Y as a function of PNN modification.&nbsp;</li> <li>Extend study to Neuronal Cells.</li> <li>Determine a biomechanical model to describe PNN behaviour.</li> </ol> <p>The project will involve the development of microfluidics, high-speed imaging and require close collaboration between Physics and Biology.</p> <p><strong>Reference:</strong></p> <p>1. Armistead FJ, Gala De Pablo J, Gadelha H, Evans, SD Cells Under Stress: An Inertial-Shear Microfluidic Determination of Cell Behavior.&nbsp;<em>Biophys J</em>&nbsp;2019;116(6):1127-36. doi: 10.1016/j.bpj.2019.01.034&nbsp;</p>

<h2 class="heading">How to apply</h2>

<p>Formal applications for research degree study should be made online through the&nbsp;<a href="http://www.leeds.ac.uk/rsa/prospective_students/apply/I_want_to_apply.html">University&#39;s website</a>. Please state clearly in the research information section&nbsp;that the research degree you wish to be considered for is ICell Deformation Cytometry for Studying of the Role of Perineuronal Nets in controlling the Biomechanics of Neuronal Cells. as well as&nbsp;Stephen Evans as your proposed supervisor.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <p><em>We welcome applications from all suitably-qualified candidates, but UK black and minority ethnic (BME) researchers are currently under-represented in our Postgraduate Research community, and we would therefore particularly encourage applications from UK BME candidates. All scholarships will be awarded on the basis of merit.</em></p>

<h2 class="heading heading--sm">Entry requirements</h2>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

<h2 class="heading heading--sm">English language requirements</h2>

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.

<h2 class="heading">Funding on offer</h2>

<p>A highly competitive EPSRC Doctoral Training Partnership Studentship consisting of<strong>&nbsp;</strong>the award of fees with a maintenance grant of &pound;15,285 (currently for session 2020/21) for 3.5 years.&nbsp;</p> <p>This opportunity is open to all applicants, with a small number of awards for Non-UK applicants limited by UKRI to 1.&nbsp; All candidates will be placed into the EPSRC Doctoral Training Partnership Studentship&nbsp;and selection is based on academic merit.</p> <p>This project is also eligible for the School of Physics &amp; Astronomy Fee Only award.</p> <p>The <a href="https://www.ukcisa.org.uk/">UKCISA</a> website will be updated in due course with information regarding Fee Status for Non-UK Nationals starting from September/October 2021.</p>

<h2 class="heading">Contact details</h2>

<p>For further information regarding your application, please contact Doctoral College Admission, e:&nbsp;&nbsp;<a href="mailto:maps.pgr.admissions@leeds.ac.uk">maps.pgr.admissions@leeds.ac.uk</a></p> <p>For further information regarding the project, please contact Professor Stephen Evans,<br /> e:&nbsp;<a href="mailto:EMAIL@leeds.ac.uk">s.d.evans@leeds.ac.uk</a>, t: +44 (0)113 343 3852</p>


<h3 class="heading heading--sm">Linked funding opportunities</h3>
<h3 class="heading heading--sm">Linked research areas</h3>