PhD positions

We currently have several opportunities for funded and self funded PhD positions in the lab:

(CASE Studentship) Identifying biological pathways affected by agrochemical toxicity

Principal Supervisor: Professor Chris Thompson

Funding

Funding available for eligible UK/EU applicants.

Description

Applications are invited for this PhD studentship (3.5 years) funded by a BBSRC Industrial CASE Partnership Award with Syngenta, commencing September 2015.  

Agrochemical use has led to major advances in crop production and food provision. However, many agrochemicals have toxic side effects on development that must be identified before novel agrochemicals are used. The realisation that core developmental signalling pathways exhibit deep evolutionary conservation raises the possibility that experimentally tractable model organisms, can be used to study altered developmental toxicity. Moreover, because these systems enable the perturbed pathways to be discovered, this molecular knowledge can be applied to mammalian species.

One such model organism is the social amoeba Dictyostelium discoideum. Dictyostelium cells can be easily and rapidly grown in the lab to large scales, and are amenable to microbial genetics, genomics and biochemistry. Dictyostelium studies have offered insights into the genes and pathways regulating fundamental biological processes such as chemotaxis, cytoskeletal regulation, cell adhesion and cell motility. Crucially, conserved signalling cascades drive the differentiation of fewer than 10 different cell types during multicellular development, compared to 1000s in higher organisms.

Previously, we found that different classes of Syngenta agrochemicals known to affect rodent, lagomorph, zebrafish and C. elegans development also affect Dictyostelium growth and development.

In this project you will extend this pipeline to characterize the developmental toxicity effects and molecular targets of novel Syngenta compounds

(A) Define the effects of compounds on Dictyostelium development:

You will define compounds that exhibit robust developmental effects to be taken further for more detailed studies.

(B) Determine the developmental effects of compounds at the molecular level in Dictyostelium:

(i) You will define the effects of compounds on known genes and pathways in Dictyostelium development (e.g using RNAseq). (ii) You will screen libraries of mutant Dictyostelium cells to identify molecular targets of Syngenta compounds.

(C) Translation of findings:

Datasets generated and effects will be compared to homologous genes or pathways in rodent and lagomorph development.

 

Related Publications

Wolf JB, Howie JA, Parkinson K, Gruenheit N, Melo D, Rozen D, and Thompson CRL* (2015) Fitness trade-offs result in the illusion of social success Current Biology, Apr 20;25(8):1086-90.

Parkinson K, Baines AE, Keller T, Gruenheit N, Bragg L, North RA, *Thompson CRL. (2014) Calcium-dependent regulation of Rab activation and vesicle fusion by an intracellular P2X ion channel. Nature Cell Biology. vol 16(1) p. 87-98.

Chattwood A, Nagayama K, Bolourani P, Harkin L, Kamjoo M, Weeks G, *Thompson CRL. (2013) Developmental lineage priming in Dictyostelium by heterogeneous Ras activation. eLife, vol 2:e01067.

Parkinson K., Buttery N.J., Wolf J.B. and *Thompson C.R.L (2011) A simple mechanism for complex social behavior PLoS Biology, vol9 e1001039

Blagg S.L., Battom S., Annesley S.J., Keller T., Parkinson K., Wu M-F, Fisher P.R. and *Thompson C.R.L (2011) Cell type specific filamin complex regulation by a novel class of HECT ubiquitin ligase is required for normal cell motility and patterning Development, vol 138 p. 1583-93

 

Subject Areas

  • Cell Biology
  • Developmental Biology
  • Environmental Biology
  • Evolutionary Biology
  • Gene Expression
  • Genetics
  • Microbiology
  • Molecular Biology

How to Apply

This is a fully-funded PhD studentship (fees and stipend), duration 3.5 years.  Applications should be submitted online no later than 5pm Wednesday 29 July 2015.  On the online application form select PhD Developmental Biology.  Applicants must be from within the UK or EU.  EU applicants should meet the residency requirements set by BBSRC in order to be eligible for a full award, see http://www.bbsrc.ac.uk/documents/studentship-eligibility-pdf/

Informal enquiries can be made to the Principal Supervisor, Professor Chris Thompson.

Interviews for shortlisted candidates are to be held in Manchester on Thursday 6 August 2015.

See: How to Apply

Self Funded PhD Projects

  • Cell migration and adhesion in embryonic development and disease
  • Embryonic stem cell priming and cell fate bias during development
  • Identifying and Characterizing Genes Required For Social Behaviour
  • Identifying novel drug targets for ion channel regulation
  • Whole genome sequencing to identify candidate genes governing social behaviour in Dictyostelium discoideum
Cell migration and adhesion in embryonic development and diseasePrincipal Investigators: Professor Chris ThompsonFundingProject available for individuals with self arranged funding.

Description

When cell migration goes wrong, it can have catastrophic consequences, for example resulting in cancer cell invasion. Understanding how cell migration is regulated at the molecular level is therefore important for the development of novel disease treatments and therapeutic agents. Live imaging of embryonic development, wound healing and immune responses has revealed the incredible importance of cell migration, whilst providing tools to study its role and regulation. Using these techniques we have found that cell type specific motility and adhesion during development requires the correct regulation of a small GTPase (Rap1) and the cell matrix associated protein Filamin. In this project, you will use a combination of genetics (mutagenesis), biochemistry (proteomics) and live cell imaging (3D imaging of cell movement) to identify novel genes that regulate Rap1 and Filamin complex activity, cell adhesion and cell migration.

Related Publications

  • Blagg S.L., Battom S., Annesley S.J., Keller T., Parkinson K., Wu M-F, Fisher P.R. and *Thompson C.R.L (2011)  Cell type specific filamin complex regulation by a novel class of HECT ubiquitin ligase is required for normal cell motility and patterning, Development, vol 138 p. 1583-93
  • Kay R.R. and *Thompson C.R.L. (2009) Forming patterns in development without morphogen gradients: scattered differentiation and sorting out, Cold Spring Harbor Perspectives in Biology, Generation and Interpreting Gradients p. 289-300
  • Parkinson K., Bolourani P., Traynor D., Aldren N., Kay R., Weeks G., *Thompson C.R.L. (2009)
  • Regulation of Rap1 activity is required for differential adhesion, cell-type patterning and morphogenesis in Dictyostelium. Journal of Cell Science, vol 122 p. 335-44

SubjectAreas

Biochemistry

Bioinformatics

Cell Biology

Cell Matrix Research

Developmental Biology

Gene Expression

Genetics

Fee Band

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

How to Apply

Find out How to apply for this PhD Project.

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Embryonic stem cell priming and cell fate bias during developmentPrincipal Investigators: Professor Chris ThompsonFundingProject available for individuals with self arranged funding.

Description

When stem cells are placed in a uniform signaling environment not all cells respond in the same way, and some cells do not respond at all. It is thought that this is because different cells within a seemingly uniform population are be biased or primed to respond due to their ‘epigenetic signaling history’. Understanding this priming may improve our ability to exploit stem cells in therapeutic treatments. However, little is known about the molecular basis underlying this phenomenon. ?One way to address this is to use is through studies of cell fate choice during multicellular development, especially case where cells differentiate seeming at random or stochastically in response to developmental signals. This is clearly seen in examples ranging from the early mouse embryo to the social amoeba D. discoideum. Indeed, we have recently discovered that the retinoblastoma (Rb) tumour suppressor and the Ras oncogene bias cell fate choice in the model organism D. discoideum. In this project you will study the interplay between Ras and retinoblastoma, how their activity is controlled and how these differences affect responses to the signals regulating cell fate. Two experimental approaches are possible (1) You will use cutting edge genome wide mutagenesis using a barcoded set of mutants to identify novel genes that affect bias and the regulation of Ras/retinoblastoma activity (2) You will use proteomic and genomic (transcriptome/next generation sequencing) to identify novel regulators of Ras and retinoblastoma and to establish how they exert their affects. ?The role of novel genes will be defined in D. discoideum and mammalian cells using molecular genetic (e.g. transformation, knockout GFP-fusion) and microscopy approaches (live cell imaging). Your studies, will lead to a better understanding of why cells adopt a particular fate and how this may be manipulated.

Related Publications

  • Chattwood, M.A. and *Thompson C.R.L (2011)  Non-genetic heterogeneity and cell fate choice in D. discoideum   Development, Growth and Differentiation, vol 53 p. 558-66
  • Kay R.R. and *Thompson C.R.L. (2009) Forming patterns in development without morphogen gradients: scattered differentiation and sorting out,  Cold Spring Harbor Perspectives in Biology, Generation and Interpreting Gradients p. 289-300
  • Keller T. and *Thompson C.R.L. (2008)  Cell type specificity of a diffusible inducer is determined by a GATA family transcription facto, Development, vol 135, p 1635-1645

SubjectAreas

Biochemistry

Bioinformatics

Cell Biology

Cell Matrix Research

Developmental Biology

Gene Expression

Genetics

Stem Cell Research

Fee Band

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

How to Apply

Find out How to apply for this PhD Project.

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Identifying and Characterizing Genes Required For Social BehaviourPrincipal Investigators: Professor Chris ThompsonFundingProject available for individuals with self arranged funding.

Description

Cooperative or social behaviour occurs when cells or organisms help one another. But why would it be beneficial to sacrifice yourself to help others. Why not cheat and not pay your fair share of the cost? Understanding why cooperation has evolved and is stable is a major unanswered problem in the biological sciences. We know that genes regulate social behaviour, but which ones? We also know that it must be costly to lose genes that promote cooperation, but why? Microorganisms give us the chance to answer these questions as they are often not only social, but can also be studied in the lab using post genomic or molecular genetic approaches. The social amoeba Dictyostelium discoideum is one such organism. In my lab we have begun to isolate social mutants in Dictyostelium. The aims of this project will be to identify and study the disrupted genes in one or more of these mutants. You will use cutting edge genetic (mutagenesis), biochemical (proteomic), genomic (transcriptome analysis) and microscopy approaches (live cell imaging). Through your studies, you will identify novel genes that regulate social behaviour and characterise the roles that they play.

Related Publications

SubjectAreas

Biochemistry

Bioinformatics

Cell Biology

Cell Matrix Research

Developmental Biology

Evolutionary Biology

Gene Expression

Genetics

Fee Band

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

How to Apply

Find out How to apply for this PhD Project.

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Identifying novel drug targets for ion channel regulationPrincipal Investigators: Professor Chris ThompsonFundingProject available for individuals with self arranged funding.

Description

Ion channels represent one of the major therapeutic drug targets for wide ranging diseases. For example ion channel driven cellular responses to ATP regulate diverse physiological processes in mammals, including inflammation and pain. ATP signaling by P2X receptors therefore represents a novel target for disease involving pain and inflammation, with several pharmaceutical companies actively pursuing this potential. Understanding how P2X receptors are regulated will therefore be important for the further development of such drugs. Recently we have developed a novel approach to identify such regulators due to our discovery of a novel P2X receptor in the model organism Dictyostelium discoideum. You will use the unique combination of genetic (mutageneis), biochemistry (proteomic), live cell imaging and post-genomic tools available in Dictyostelium to identify novel genes that regulate P2X receptor function. Your studies will lead to a better understanding of the role and regulation of this pharmacologically important class of molecule.

Related Publications

  • Fountain S.J., Parkinson K., Young M.T., Cao L., *Thompson C.R.L., North R.A. (2007) An intracellular P2X receptor required for osmoregulation in Dictyostelium discoideumNature, vol. 448, p. 200-3

SubjectAreas

Adaptive Organismal Biology

Biochemistry

Bioinformatics

Cell Biology

Channels & Transporters

Evolutionary Biology

Genetics

Membrane Trafficking

Microbiology

Molecular Biology

Organelle Function

Fee Band

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

How to Apply

Find out How to apply for this PhD Project.

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Whole genome sequencing to identify candidate genes governing social behaviour in Dictyostelium discoideumPrincipal Investigators: Professor Chris ThompsonFundingProject available for individuals with self arranged funding.

Description

Although the Darwinian idea of ‘survival of the fittest’ is central to our understanding of the diversity of life on this planet, the evolution and maintenance of cooperative behaviour remains a conundrum. This is because when cooperating individuals perform some sort of costly act to help one another, they run the risk of disruptive cheaters that do not pay their fair share of the cost. In other words, if cheating is a better strategy, how is cooperative behaviour maintained within populations.

To address these problems, we use a simple system for the study of cooperative behaviour, the soil dwelling social amoeba D. discoideum. Under favourable conditions, D. discoideum amoebae exist as single celled individuals that grow and divide by feeding on bacteria. Upon starvation, however, up to 100,000 amoebae aggregate and cooperate to make a multicellular fruiting body consisting of hardy spores supported by dead stalk cells. Stalk cells thus sacrifice themselves to help the dispersal of spores, raising the question of why selection does not lead to unchecked cheating by individuals that do not pay their fair share of the cost of stalk production. Indeed, we have recently found that even within a small number of different D. discoideum strains, different social strategies, including facultative partner specific cheating and coercion, could be detected.

However, the key will be to extend this work to address patterns of genetic variation at the molecular genomic level in natural populations.

Through this PhD studentship we aim to reach this important goal. The project will have 3 stages:

1. Genome sequencing: Whole genome sequence data will be generated for many different naturally occurring D. discoideum isolates

2. Bioinformatic analysis of this sequence data: This will allow you to test whether genetic variation is associated with patterns of phenotypic variation. Through this you will identify ‘social genes’ and the potential role of all of these genes as generators of biodiversity. Finally, these data will allow broader questions regarding the selective forces driving genome evolution and the emergence of social traits to be addressed.

3. Molecular genetics: Using cutting edge developmental genetics techniques (e.g. transformation, knockouts and forced expression of functional variants) you will test hypotheses about the functional consequences of sequence variation on social behaviour.

In summary, this project will address major questions in evolutionary, developmental and environmental ecology. It will utilise hugely multidisciplinary approach by combining next generation sequencing, bioinformatic exploration of sequence variation, together with molecular and developmental genetics. Consequently it will undoubtedly provide an unprecedented opportunity for training in multidisciplinary approaches to biological questions.

Related Publications

  •  Parkinson K., Buttery N.J., Wolf J.B. and Thompson C.R.L (2011) A simple mechanism for complex social behaviour. PLoS Biology, vol9 e1001039
  • Buttery N.J., Thompson C.R.L, Wolf J.B. (2010) Complex genotype interactions influence social fitness during the developmental phase of the social amoeba Dictyostelium discoideum. Journal of Evolutionary Biology, vol 23 p.1664-71.
  • Buttery N.J., Rozen D.E., Wolf J.B., Thompson C.R.L. (2009) Quantification of social behavior in D. discoideum reveals complex fixed and facultative strategies. Current Biology, vol 19 p. 1373-7
  • Santorelli L., Thompson C.R.L., Villegas E., Svetz J, Dinh C., Parikh A., Sucgang R., Kuspa A., Strassman J.E., Queller D.C., Shaulsky G. (2008) Facultative cheater mutants reveal the genetic complexity of cooperation in social amoebae. Nature, vol 451, p 1107-10
  • Foster K.R., Shaulsky G., Strassmann J.E., Queller D.C., Thompson C.R.L. (2004) Pleiotropy as a mechanism to stabilize        cooperation.. Nature, vol. 431, p. 693-6

SubjectAreas

Adaptive Organismal Biology

Biochemistry

Bioinformatics

Cell Biology

Channels & Transporters

Evolutionary Biology

Genetics

Membrane Trafficking

Microbiology

Molecular Biology

Organelle Function

Fee Band

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

How to Apply

Find out How to apply for this PhD Project.

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