Faculty of Biological Sciences

Faculty of Biological Sciences
Summer Vacation Studentship Opportunities 2018

Are you interested in working in a Research Laboratory during the summer vacation?

We are offering the opportunity to work in a research laboratory during the summer vacation. This type of experience is ideal if you are thinking of continuing with a career in research after graduating, or if you would like to find out what research is all about.

Under these schemes the laboratories offer experimental projects in a wide variety of subject areas and last up to 8 weeks. The stipends available are approximately £200 per week.

This year, the faculty will be supporting three different schemes; Dean's Vacation Research Studentships, Summer Vacation Studentships & Jennifer Rowles Studentships. Please see below for more information.

Eligible Students:

Science Students and Medical Students between the end of their second year and the end of their penultimate year (but not intercalating students).

Only students registered at a UK university are eligible to apply.

Please note that the Jennifer Rowles Studentship scheme is only open to University of Leeds students.

Closing dates:

The closing dates for all schemes will be 12 noon on Thursday 25th January.

Applications Procedure:

Please send your application by email, selecting one or two projects in order of preference, to Rebecca Pollitt (r.e.pollitt@leeds.ac.uk).

Please note that you are able to apply for more than one scheme, but no more than two projects in total.

Students are chosen for Studentships by competition, so your application should consist of a curriculum vitae and letter including;

  • The title(s) of the the project(s) you are interested in. You may apply for more than one project, but please list in order of preference
  • Your school and university courses and grades to date
  • A statement of your career aims and how you might benefit from a Scholarship
  • The name, address, phone number and email addresses of two referees, preferably your tutors

Funding

Dean's Vacation Research Studentships

These projects are offered by Faculty postdocs and internally funded.  Applicants will be shortlisted and invited for interview.  Successful candidates will be supervised in the lab by the postdoc leading the project.

Jennifer Rowles Studentships

These projects are internally funded and only open to University of Leeds students.  Candidates will be selected by the academic leading the project, based on their application and CV and may be invited to take part in an informal interview.

Summer Vacation Studentships

These projects are subject to a successful application for external funding.  Candidates will be selected by the academic leading the project, based on their application and CV and may be invited to take part in an informal interview.  Successful candidates will then work with the academic to submit an application to an external funding body to support the studentship.

 

Dean's Vacation Projects

 

Project Leader / Project Docs

Project Details

Chi-Chuan

 


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A biophysical characterisation of the FGFR2-CRKL interaction

The adaptor protein CRKL is required in receptor tyrosine kinase (RTK)-mediated signal transduction. It regulates the malignant potential of human cancer by controlling several biological processes including cell proliferation, migration, gene expression and apoptosis.

CRKL consists of one SH2 and two SH3 domains. Under physiological conditions, CRKL interacts with tyrosine phosphorylated receptors through its SH2 domain and activates the small G proteins Rac1 and Cdc42, as well as their effector PAK. This pathway is a feed-forward loop that feeds into the MAPK pathway. Overexpression of CRLK results in the upregulation of FGF receptor-mediated Erk1/2 and PI3/AKT pathways and contributes to breast cancer and pancreatic cancer progression. While it is a target for cancer therapeutics, the precise role of CRKL in RTK signalling has been unclear.

Recently we have reported that cells which are not exposed to high concentrations of extracellular stimuli maintain a low level of background signalling transduced by growth factor receptor (FGFR2)-mediated early signal complex through its proline-rich motif recruiting SH3 domain-containing proteins. We are particularly interested in the role that this signalling plays in oncogenesis. This project will be focused on the investigation of the CRLK SH3 domain-mediated interaction with FGFR2 and its oncogenic functional outcome under basal conditions.

 

Celia Ferreira

 


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Control of muscle contraction in Caenorhabditis elegans of relevance to human malignant hyperthermia, exertional heatstroke and muscle ageing

The ryanodine receptor (RyR) is the sarcoplasmic reticulum Ca2+ channel involved in muscle contraction. Our work revealed single amino acid changes in the >5000 residue Caenorhabditis elegans RyR (encoded by unc-68), equivalent to human myopathic variants, which result in compromised Ca2+ transport and decreased lifespan. RyRs have a corresponding function in endoplasmic reticulum of nonmuscle cells, and we found that the altered phenotypes also involve nerve cell function. Furthermore, our mutagenesis screen revealed CLA-1, the homologue of human Piccolo involved in neurotransmitter release, to function in concert with UNC-68.

Numerous links have been made between Ca2+ control, mitochondrial function, reactive oxygen species (ROS) and ageing. Mitochondria generate ROS, alongside ATP production, and act as an intracellular Ca2+buffer. Conversely, Ca2+ regulates mitochondrial function. In aged humans, RyRs become leaky, affecting Ca2+ levels (Lamboley et al (‘16) J Physiol 594, 469-81). Mitochondria and muscle Ca2+ release units are functionally linked through a physical tethering, which reduces with age in mice and humans (Pietrangelo et al (‘15) Oncotarget 6, 35358). Aging is the primary risk-factor for many neurodegenerative-diseases, including Alzheimer’s. We propose to assess ROS levels and oxidative stress state of unc-68 variant and unc-68 cla-1 double mutant strains across the lifespan.

 

Antoine Larrieu

 


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Robustness in Plants

A striking feature of flowers in higher plants is their uniformity: their shape and size can be predicted with a high degree of certainty in single species. These traits are furthermore independent of variations in environmental conditions. The genetic model for flower development shows how four sets of related transcription factors (TFs) can combine to define the identity of the four floral organs (sepals, petals, stamens and carpels). One of these sets, known as the E-function, is present in multiple paralogous copies throughout flowering plants, despite there being no mechanistic explanation for this diversification.

The four paralogous copies of the E-function genes present in Arabidopsis (called SEPALLATA1-4) are essentially redundant, since phenotypes of single mutants have been described as subtle or absent. However, by combining state of the art growth, phenotyping and molecular analyses the team has showed that E-function mutants have dramatic floral phenotypes with a striking loss of fitness when grown in perturbed conditions.

The aim of this research grant is to understand how E-function genes can buffer floral development under different environmental conditions. Essential to their activity, these genes are highly regulated at the transcriptional level, displaying specific expression patterns. How this is achieved has been unexplored.

 

Marianne Mugabo

 


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Interactions between sources of environmental change: How do resource quality and coloured environments modify multi-trophic eco-evolutionary dynamics?

My research grant is funded by NERC and is a collaboration between researchers at the University of Leeds and Swansea University. Our research project focuses on the effects of habitat degradation and climate change on the ecological and evolutionary dynamics of a host-parasitoid model system. Habitat degradation and climate change are two of the main environmental drivers responsible for the current biodiversity crisis. For instance, there is considerable evidence that the recent climate change has led to significant species responses such as shifts in their distribution ranges and local extinctions. However, there is still a gap in our understanding of how they affect trophic interactions between species (e.g., predator-prey, host-parasitoid), which play a fundamental role in ecosystem functioning and ecosystem services.

To address this key question in Ecology, we use experimental and mathematical approaches which are tightly integrated. More specifically, the Leeds team designs and carries out short-term and long-term life history and population dynamics experiments to obtain detailed measures of individual and population responses to resource quality (a proxy for habitat degradation) and temperature variation which are then used by the Swansea team to develop complex population models to predict their long-term effects on host and parasitoid population dynamics.

 

Miriam Walden

 


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Functional studies and inhibition of deubiquitinating (DUB) enzymes

Ubiquitination is a key regulator of protein activity, function and stability. It plays a major role in cellular processes including signal transduction and proteasomal degradation. Ubiquitinmediated signalling is controlled by the opposing activities of E3 ubiquitin ligases which conjugate ubiquitin to a protein, and deubiquitinating enzymes (DUBs), which remove ubiquitin from substrates. DUBs and their regulators are frequently mutated in cancer, neurodegeneration, inflammation and other human diseases.

DUBs are divided into six families, one of which is the Zn2+-dependent JAMM/MPN family. MPN DUBs typically function within larger multi-subunit complexes, which imparts great potential for multi-layer regulation. MPNs often require interactions with accessory subunits to be catalytically active and for subcellular localisation. Our goal is to gain insights into the control and cellular roles of these DUB enzymes. A major focus will be on identifying and dissecting the mechanism of action of DUBs and their inhibitors. We use crystallography and cryo-EM techniques in combination with biochemical and biophysical analyses to determine the structure and investigate the function and regulation of DUBs. One such DUB is BRCC36 which is part of a 280 kDa 4-subunit complex called BRISC. How BRCC36 is activated and what regulates BRISC activity remains an open question.

 

 

 

Jennifer Rowles Projects:

 

Project Leader

Project Details

Jim Deuchars

Identifying and modulating production of new cells in the spinal cord

We have recently discovered that we can use particular chemicals to induce or reduce the production of new cells in the spinal cord. In the long term we hope to harness this neurogenesis to repair conditions in which the spinal cord malfunctions, such as in spinal cord injury, motor neuron diseases or multiple sclerosis. This project will investigate the effects of particular treatments on neurogliogenesis in the spinal cord, aiming to convert the new cells to neurones and/or glia.

Techniques: Tissue culture, immunohistochemistry, confocal microscopy, histological tissue sectioning

 

Ian Wood

Therapeutic potential of HDAC inhibitors for multiple sclerosis.

Recently, inhibitors of histone deacetylase enzymes (HDACs) have been identified as having potential therapeutic value for a range of neuronal disorders including multiple sclerosis and other neurodegenerative diseases [1, 2]. The HDAC inhibitors have been shown to have neuroprotective and anti-inflammatory properties yet their mechanism of action remains unidentified. We have recently shown that microglia activation by a number of insults (eg LPS, interferon and Amyloid beta) can be reduced by HDAC inhibitors [1]. Using siRNA we have identified HDAC1 and HDAC2 as the important HDAC enzymes for this response [1]. Whilst still don’t know the mechanism by which HDAC inhibitors block microglia activation we have shown that it doesn’t require new protein synthesis so is unlikely to be a result of the well characterised effect of these inhibitors on increasing gene expression.  We are currently investigating the cellular mechanism(s) involved in the inhibition and identifying the molecular targets involved. The approach will involve the use of cell culture methods, functional assays to quantify cell responses such as proliferation as well as molecular approaches to quantify cytokine production and changes in gene and protein expression.

1. Durham, B.S., R. Grigg, and I.C. Wood, Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism. J Neurochem, 2017.

 

 

 

Faculty Vacation Projects

 

Project Leader

Project Details

Stuart Egginton

Extreme cardiovascular physiology – explaining cardiac function in severely dilated hearts

A major problem in cardiovascular science is understanding how to cope with enlarged hearts as a result of disease that inevitably results in compromised function, sometimes fatally e.g. dilated cardiomyopathy (DCM, affects 1 in 250 people). Potential mechanisms to counteract ventricle volume and still preserve adequate cardiac output include adjustments in proteins associated with sarcomere structure. One of the most important of these, titin, constitutes about 10% of muscle mass, and is the third most abundant protein after actin and myosin. Titin errors are the commonest cause of DCM (~25% of cases) with damaging mutations mainly in the A-band region, indicating a compromised interaction with myosin.

This project offers a student the opportunity to work in one of the world’s leading labs examining how molecular structure defines muscle function (http://www.fbs.leeds.ac.uk/staff/profile.php?tag=Trinick), using cardiac samples from a unique groups of animals lacking respiratory pigment expression (http://www.fbs.leeds.ac.uk/staff/profile.php?tag=Egginton_S).  These icefishes have a ventricle size approximately 4 times that of related species, and are capable of generating huge stroke volumes. How this is achieved is a mystery. We will examine the titin content of these fishes and attempt to understand the highly unusual capacity for force development at high volumes, exploring whether or not this elastic component is essential for white hearts to function effectively.

The student will experience analytical protein chemistry by means of separation, electrophoresis and antibody selection, compare findings with new samples fixed for examination of sarcomere structure under the EM, and correlate results with recent data on in situ function of these amazing hearts, obtained for the first time on a recent Antarctic field-trip.

 

Isuru Jayasinghe

Molecular-scale mapping of ryanodine receptor arrays and membrane networks in mammalian (and human) skeletal muscle

Fast and forceful contraction of skeletal muscle underpins our ability to move, breathe and maintain posture. At the cellular level, this contraction is enabled by vast quantities of calcium released in a highly synchronised manner from the internal calcium stores. Regular arrays of calcium channels called Ryanodine Receptors (RyR) located throughout the fibres are the main source of this calcium release. Synchronising the RyR activity, is a highly intricate network of plasmalemmal extensions called the t-system. In both animals and humans, mutations to the proteins which form the structural and functional links between the t-system and RyR can lead to re-arrangement of these nanostructures. The consequences can range from mild muscle weakness to devastating muscle degeneration conditions.

During this studentship, you will apply the novel super-resolution microscopy technique called dSTORM to mapping the location of RyRs against the t-system within rodent skeletal muscle at a resolution no worse than electron microscopy. This will involve dissecting skeletal muscles from the hind limbs and preparing them for immunofluorescent staining. Stained tissue sections will be subjected to single molecule imaging. Computer-based analysis of the acquired imagers will allow you to construct density maps of RyRs in these fibres. Once you have established the methodology to image, map and analyse the RyR positions in rodent muscle, you will study muscle biopsies obtained from human subjects carrying inherited muscle degeneration conditions.

As an outcome of the studentship, you will document, for the first time, the molecular-scale rearrangement of RyRs and t-tubules in degenerating skeletal muscle conditions. You will gain hands-on experience with the state-of-the-art super-resolution microscopy techniques and an opportunity to contribute to a peer-reviewed publication.

 

Lars Jeuken

Development of enzyme-based hydrogen-oxygen fuel cells

Fuel cells are a type of battery in which the electrical energy is stored in the forms of a (transportable) fuel. The best-known example of this is the hydrogen fuel cell, which forms the core of current-day technologies such as the hydrogen car. Current hydrogen-oxygen fuel cells (HOFCs) rely on a rare and precious noble metal catalyst, platinum, to catalyse the oxidation of hydrogen to hydrogen ions (protons). Hydrogenases are a class of biocatalyst that perform the same reactions using cheap, earth-abundant metals (nickel and iron) and have long been acknowledged as promising biocatalysts for HOFCs, potentially reducing their production cost.

Commercial exploitation of hydrogenase-based HOFCs has been limited by the cost of enzyme purification, limited durability of the purified enzyme and a previously observed sensitivity towards oxygen (i.e., activity of hydrogenase in HOFCs is irreversibly inhibited by the presence of oxygen). As part of the previous research in the Jeuken Group, a novel technology has been developed that shows that, in principle, these limitations can be overcome if a membrane-bound form of hydrogenase is used. In this summer project you will investigate if membrane-bound hydrogenases could be used a biocatalyst in HOFCs.

Heath, G.R., Li, M., Rong, H., Radu, V., Frielingsdorf, S., Lenz, O., Butt, J.N., Jeuken, L.J.C. (2017) Multilayered lipid membrane stacks for biocatalysis using membrane enzymes. Adv. Funct. Mat., 27, Art. No. 1606265. DOI: 10.1002/adfm.201606265

Radu, V., Frielingsdorf, S., Evans, S.D., Lenz, O., Jeuken, L.J.C. (2014) Enhanced Oxygen-Tolerance of the Full Heterotrimeric Membrane-Bound [NiFe]-Hydrogenase of Ralstonia eutropha, J. Am. Chem. Soc., 136, 8512-8515. DOI: 10.1021/ja503138p Spotlight:DOI: 10.1021/ja5060466

 

Ralf Richter

Revealing how signalling proteins move in the extracellular space to communicate between cells

The extracellular matrix (ECM) is a highly dynamic network which not only provides structural support to cells but also helps regulate intracellular signalling cascades and biochemical reactions. The ECM is composed of a plethora of structural components and signalling molecules, and we aim to probe individual elements of this in order to gain an insight into the molecular mechanisms that can lead to diseases such as cancer metastasis or chronic inflammation.

Model matrices that are made of selective ECM components enable us to single out desired interactions and remove the interference which would be present in cellular systems thus making them attractive alternatives. Our intention is to characterise how chemokines move and interact within the ECM in relation to glycosaminoglycans (GAGs). GAGs are extracellular polysaccharides that harbour signalling proteins such as cytokines and control their distribution and availability to help attract immune cells as part of the inflammatory response.

The project will entail the design and optimisation of producing fluorescently tagged cytokines that can be presented to model matrices for characterisation using a range of quantitative biophysical methods. This will be a multi-disciplinary project where you will learn elements of molecular and cellular biology as well as biophysical techniques to provide new insight on the mobility and interactions of cytokines.

We are looking for an enthusiastic and determined student to take on this project. Experience in molecular or cellular biology, or biophysics are desirable however, not essential. The ideal candidate will be able to critically analyse and assess results and techniques used, and able to work well individually and as part of a team.

 

Rao Sivaprasadrao

The aim of the project is to investigate the role of calcium channels in cell cycle and cancer cell proliferation. During the cell division, besides the nucleus, other organelles, including the mitochondria, are distributed equally between the dividing daughter cells. In most cells, however, mitochondria exist as a reticular network; this makes the division of the network to smaller fragments indispensable to allow their distribution between the dividing cells. Calcium plays an important role in mitochondrial fission, but its role during the cell cycle is poorly understood. The objective of the study is to examine the roles of various calcium channels in mitochondrial fission during cell division using cell lines that express fluorescent proteins capable of reporting the various stages of the cell cycle and mitochondrial fission. The project involves cell culture, DNA transfections, fluorescent microscopy, and data analysis using Image J and Origin.