Example Projects

The table below lists examples of current DTP projects and of recent collaborative projects involving DTP partner organisations.

  
Mechanotransduction in developing tissues

Student - Karolis Leonavicius, DTP Cohort 2012
Supervisors – Dr Shankar Srinivas, Prof. Fritz Vollrath
Department of Physiology, Anatomy and Genetics & Department of Zoology

Cell position sensing in a mouse embryo
Mammalian development is a time of rapid change, when stem cells proliferate and progressively differentiate to create new emerging tissues. These processes happen in complex geometric environments and the role it plays is not fully understood due to lack of experimental techniques. We create novel 3D cell culture and microscopy assays to study how tissue geometry regulates mouse embryo and stem cell development. Fully understanding tissue mechanics is crucial for complementing our current knowledge of developmental biology and its applications for tissue engineering.
The independent evolution of plant roots within the lycophyte lineage
Student – Sandy Hetherington, DTP Cohort 2012
Supervisors – Prof. Liam Dolan, Dr Steve Kelly
Department of Plant Sciences

The aquatic lycophyte Isoetes echinospora © Sandy Hetherington 2014
Roots provide the primary interface between land plants and the terrestrial surface. Biologically, the evolution of roots allowed plants to increase in height, leading to the evolution of trees in the Devonian period circa 400 million years ago. For such an important innovation it might, therefore, seem surprising that when fossils are examined within a phylogenetic context it is clear that roots have evolved independently in two of the major lineages of land plants: the lycophytes (clubmosses) and the euphyllophytes (ferns and angiosperms). There is an emerging mechanistic understanding of root development in euphyllophytes, largely through work on the model plant Arabidopsis thaliana. However, the genetic basis of the control of root development and epidermal patterning in the lycophytes is unknown. The current study will use next generation sequencing to identify the first putative regulators controlling lycophyte root development. To do this a lycophyte Isoetes will be characterised; chosen because of its fascinating evolutionary history and unique rooting organ. The project will aim to test whether the independent origin of land plant roots was the product of de-novo gene diversification or modification of a pre-existing genetic network.
How does lipase immobilisation on various surfaces impact structural stability, dynamics and interactions?
Student – Nathalie Willems, DTP Cohort 2012
Supervisor: Prof. Mark Sansom
Department of Biochemistry

Lipase interacting with a lipase bilayer
The immobilisation of enzymes has revolutionised the biotechnology industry to date. The main challenges for the continued development of enzyme immobilisation include optimising enzyme stability and activity on the surface used for immobilisation. We use molecular dynamics simulations to study how lipase enzymes interact with a range of surfaces of varying structural characteristics. This information is used to assess how the surfaces affect the conformational dynamics of these enzymes, with the aim of predicting which enzyme-surface interactions are optimal in the context of enzyme immobilisation.

Structural and dynamical studies of enzymesStudent – Michael Barber, DTP Cohort 2012
Supervisors – Andrew Baldwin & Robert Gilbert
Department of Physical and Theoretical Chemistry & Nuffield Department of Medicine/STRUBI

Function from motion
The structure and dynamics of proteins are key to understanding their biological functions. This project involves an interdisciplinary approach to structural studies, complementing X-ray crystallography, EM and Mass spectrometry with recently developed ‘high molecular weight’ NMR. Structural data from these techniques coupled with functional data will generate novel insights into biologically interesting systems associated with fundamental biological processes. These systems include: 1) terminal uridylyl transferases, which were recently demonstrated to play a pivotal role in RNA metabolism, and 2) Glucocerebrosidase, a lysosomal protein. Elucidation of structure and dynamics in these systems will allow a fuller understanding of their biological role.
The biological function of TMEM115 in lipid metabolismStudent – Xin Shen, DTP Cohort 2013
Supervisor - Prof. Matthew Freeman, Dunn School of Pathology
TMEM115 is a newly identified enzymatically inactive member of the rhomboid-like superfamily. So far, six clans of inactive homologues have been recognized: iRhoms, derlins, UBAC2, RHBDD2, RHBDD3 and TMEM115. Although TMEM115 is poorly studied, intriguing preliminary data suggest important biological functions. Firstly, TMEM115 is highly conserved from plants to humans. Furthermore, the loss of TMEM115 in mice causes a severe phenotype. Finally, a screen with the yeast TMEM115 orthologue has identified that TMEM115 genetically interacts with several lipid metabolism related genes. In addition, three lipid metabolism related proteins, NEO1, LPP1 and CPT1, have been identified as physical interactors of TMEM115 in yeast. The aim of this project is to investigate the role of TMEM115 specifically in lipid metabolism using genetics, cell biology, biochemistry and metabolomics approaches in human cell lines, Tmem115 knockout mouse tissue and embryonic fibroblasts. This work should contribute new insights into the role of the inactive rhomboid-like proteins and the field of lipid metabolism.
Age related changes in the gut microbiota and adipocytes and their modulation with anti-ageing compoundsStudent – Nicola Fox, DTP Cohort 2012
Supervisor: Prof. Jane Mellor
Department of Biochemistry

Lipid accumulation in 3T3-L1 adipocytes (stained with oil red O)
Ageing is a highly conserved process, from yeast to humans, and common mechanisms underlie seemingly different ageing characteristics. Ageing is an experimentally malleable process and many compounds have been found to influence the rate of ageing. Investigating the cellular and organismal processes that these compounds interact with and the specific genes targeted can identify pathways which may be common to the general ageing process. This project focuses on the effects of anti-ageing compounds on adipose tissue and the gut microbiota. Adipose tissue dysfunction is both a characteristic of ageing and a contributing factor to several age-related disorders, including insulin resistance, type II diabetes and atherosclerosis. Ageing and disorders including obesity are associated with changes in the population of gut bacteria, and there is evidence that gut microbiota can influence host health.
The role of potential regulators of Kranz anatomy of leaf developmentStudent – Thomas Hughes, DTP Cohort 2012
Supervisors – Prof. Jane Langdale Dr. Steve Kelly
Department of Plant Sciences

Kranz anatomy patterning during early leaf development.
It has been predicted that rice yields need to increase by 50% by 2050, however currently yields are plateauing. Rice, like the majority of plants, uses C3 photosynthesis to fix inorganic carbon dioxide (CO2) into carbohydrates. C3 photosynthesis evolved when atmospheric oxygen (O2) levels were low, and thus Rubisco, the primary enzyme responsible for CO2 fixation, did not evolve to efficiently distinguish CO2 from O2. However, an evolutionary innovation termed C4 photosynthesis has allowed many plants to overcome the inefficiencies of C3 photosynthesis. C4 species take advantage of specialised leaf anatomy, termed ‘Kranz’ anatomy, which enables CO2 to be concentrated around Rubisco in bundle sheath cells surrounding the veins. This suppresses the costly oxidation reaction, and results in C4 plants often exhibiting 50% greater yields. This has led to the suggestion that rice should be engineered to use C4 photosynthesis rather than C3. However, our understanding of how the development of Kranz anatomy is regulated is extremely limited. Recently, a transcriptomics comparison in maize has identified many candidate genes that may regulate the development of Kranz anatomy. This project will elucidate the function of a subset of C2H2 zinc-finger transcription factors that have emerged from this work.
The ecological and evolutionary constraints of ecosystem service provision to agricultureStudent – Zia Mehrabi, DTP Cohort 2012
Supervisor: Prof. Kathy Willis
Department of Zoology

Maize fields, Katanga, Democratic Republic of Congo
Agriculture is the single most dominant force by which humans impact the planet. As agriculture continues to expand, natural habitat continues to be lost. These losses of natural habitat can have direct negative feedbacks on food security through climatic disturbances and diminished ecosystem service provision to agriculture. There is a need to identify the optimal land use in agricultural landscapes to maintain biodiversity conservation and continued delivery of ecosystem services to multiple stakeholders in agricultural landscapes. This project takes a trait based approach, using local scale ecosystem functioning experiments alongside landscape-scale modelling of ecosystem processes, to understand how to maximise ecosystem service supply in agricultural systems. A key focus will be on understanding how resilience in fragmented natural habitats supports ecosystem service provision to agriculture and holds the potential to alleviate food insecurity within sub-Saharan Africa.
Exploiting peptide-protein interactions to build novel biosensors and switchesStudent – Richard Perez-Storey, DTP Cohort 2013
Supervisors – Profs. Lee Sweetlove, Phil Poole, Mark Fricker and Mark Sansom
Department of Plant Sciences & Department of Biochemistry

A novel transcriptional sensor
This project proposes a generalized, modular design of ligand-sensitive transcriptional switches in bacteria, and aims to sequentially test: a proof-of-principle of the design, using known and characterized domains; the ability of the design to be generalized; and a demonstration of the application of such a switch by driving a beneficial bacterial-root interaction. Additionally, the design could be adapted to produce FRET biosensors, which will also be tested. This project aims to facilitate the easy construction of transcriptional switches and biosensors in a “target molecule first” perspective, allowing for the production of novel biological parts with standardized outputs from a common framework.
Sexual behaviour and relatedness: from theory to insectsStudent – Sally Le Page, DTP Cohort 2013
Supervisors: Prof. Stuart West, Dr. Stuart Wigby
Department of Zoology

Mating Drosophila melanogaster during behavioural trials © Sally Le Page 2014
Evolutionary biology has been very successful in describing how the relatedness of individuals should affect their behaviour (kin selection) and how individuals should interact to obtain matings and reproduce (sexual selection). However, there has been very little communication between these two fields, leaving us less certain about how related individuals behave during reproductive events, or the mechanistic basis. This project aims to examine the mechanisms underlying male and female responses to relatedness and group size both before mating (e.g. courtship and aggression behaviours) and after mating (e.g. ejaculate composition, paternity and reproductive ageing). The project uses the fruit fly Drosophila melanogaster as a biological model and kin selection theoretical models to test how the population structure affects behaviour, ageing and its evolutionary consequences.
Overcoming antigenic variability of African Horse Sickness virus using a vaccination strategy based on epitope deletionStudent - Nicola Manning
Supervisors: Dr Javier Castillo-Olivares & Prof Sarah Gilbert
The Pirbright Institute & Nuffield Department of Medicine/Jenner Institute

Midge transmitting African Horse Sickness
African horse sickness virus (AHSV) is an arbovirus that causes a lethal disease in horses. The vaccines that are currently commercially available against AHSV contain attenuated virus strains. However, their use is compromised by the risk of reversion to virulence via gene segment re-assortment between vaccine and field strains, and a potential for transmission in the field. The drawbacks of inactivated and live AHSV vaccines have stimulated the development of novel vaccines based on recombinant DNA technology. Capsid components, in particular VP2, expressed in baculovirus have been shown to be efficacious as vaccines. However, these proteins are difficult to purify and so the baculovirus approach has yet to be commercialised. One possible strategy is the deletion of hypervariable antigenic domains from VP2, to shift the specificity of the immune response away from type-specific epitopes, towards more conserved and cross-reactive ones. The main objective of this project is therefore to generate AHSV-VP2 based proteins devoid of type-specific hypervariable domains, to immunise horses and mice and determine whether the immunodominance of variable epitopes is shifted towards conserved ones confering heterotypic immunity.
Recombinant vaccines for African Horse Sickness based on baculovirus pseudotyping and transductionStudent: Mine Aksular
Supervisors: Dr Javier Castillo-Olivares
Prof. Linda King
The Pirbright Institute & Oxford Brookes University

Biting midges
African horse sickness is an infectious, non-contagious, insect vector-borne disease of equids caused by African Horse Sickness Virus (AHSV) with more than 90% mortality rates in infected horses. The main aim of this project is to develop novel recombinant vaccines against African Horse Sickness virus based on baculovirus pseudotyping and transduction of equine cells. Baculoviruses are insect-specific, double-stranded DNA viruses that show promise as safe vaccine vectors. The AHSV genome consists of 10 double-stranded RNA segments surrounded by a double-layered capsid. The outer capsid is composed of two major proteins, one of which is VP2, which is the main serotype-specific antigen carrying the virus neutralizing epitopes. The main objectives of this project are therefore to generate modified baculovirus particles that display the AHSV VP2 protein or sub-domains thereof in their envelope (pseudotyping) and to generate baculoviruses that express AHSV VP2 within mammalian cells after transduction. Both types of recombinant baculoviruses will be explored as vaccine candidates for AHSV.
Interaction between the neurovirulence protein from herpesvirus and the ER-resident transcription factorStudent: Keshalini Sabaratnam
Supervisors: Dr Abdou Tahirir-Alaoui, Prof. Jonathan Grimes and Prof Ray Owens
The Pirbright Institute & Nuffield Department of Medicine/STRUBI

MDV infected cell (green) expressing viral protein pp14
Marek’s disease virus (MDV) is an oncogenic herpesvirus that causes various syndromes in its natural host, chicken. MDV is one of the most important and widespread infectious disease in chicken. As in other herpesvirus, MDV-gene expression is temporal. The initial viral genes that are expressed before DNA replication encode proteins that affect cellular processes to prepare the cell to execute viral DNA and protein expression, survive the stress of the infection and control the temporal order of subsequent viral or even host gene expression. These are called immediate-early genes or proteins. An example of such protein in MDV1 is phosphoprotein-14 or (pp14). pp14 is not required for viral replication nor it is associated with the oncogenic phenotype of the virus. However there is strong evidence suggesting the involvement of pp14 in viral neurovirulence. cAMP Response Element-Binding protein 3 (CREB3) has been identified as an interacting partner of pp14. CREB3 is a membrane-bound transcription factor that has recently been shown to be activated by DNA and RNA viruses’ infection. The aim of this project is to use an ensemble of biochemical, reverse genetic and structural approaches to derive new knowledge in CREB3-mediated transcriptional regulation with the hope of designing new strategies in the intervention of animal and human diseases.