英國高校最新PhD職位信息(12/09)

英國牛津大學

Dissecting the Crosstalk Between Cancer Stem Cell, Fibroblast and Immune Cell

Deadine: January 08, 2021

About the Project

Many cancers are driven by cancer stem cells (CSCs) that have the unique ability to initiate new tumour growth. The CSCs resemble partly to naturally occurring stem cells and are exceptionally important because their developmental plasticity allows them to metastasize and give rise to whole tumours in the organism (1-6). The clinical implication of CSCs is that a successful therapeutic strategy would have to eliminate this population in order to be curative. However CSCs are resistant to conventional treatments due to high expression of drug efflux pumps, anti-apoptotic properties, and enhanced DNA repair mechanisms. In addition, due to their immunomodulating features such as high level of PD-L1 expression (7), CSCs represent a key component of tumour immune evasion. Therefore, alternative strategies are required in order to target and eradicate CSCs.

Tumours including PDAC are surrounded and infiltrated by a complex tumour microenvironment including cancer-associated fibroblasts and immune cells such as T cells, macrophages and B cells. Evidence from the literature and our own data suggests that certain stromal cells such as fibroblasts may promote CSCs while other cells, particularly cytotoxic T lymphocytes, suppress tumour formation. Cells in the tumour microenvironment release ligands for several pathways normally active in embryonic development (e.g. TGFβ/Activin/Nodal) that are in turn known to promote stem-like properties in cancer. The downstream mechanisms by which this occurs are not fully understood but evidence suggests they are epigenetic and control gene expression via Smad2/3 transcription factors. These proteins act by binding to DNA and modulate gene expression, including up-regulation of certain stem cell factors. Hence, the crosstalk between cancer cells and different stromal cells is important for regulating tumour development by shaping cancer cell characteristics or eliminate cancer cells. The latter phenomenon, mediated by cytotoxic T cells, could be an attractive anti-cancer strategy by targeting cancer cells populations (e.g. cancer stem cells) by cell-based immune therapies.

The objective of this study is to investigate the cellular crosstalk between cancer stem cells and T lymphocytes / fibroblasts in the tumour microenvironment. We aim to establish a 3D co-culture model of human cancer (e.g. pancreatic cancer), using primary tumour samples and patient-derived immune cells from peripheral blood. Thereafter, we will use a range of functional and mechanistic studies for characterising the co-culture effects on cellular phenotype and gene expression of cancer cells and immune cells with the aim to identify key regulatory factor(s) within the crosstalk network. Lastly, we will test the translational potentials of killing CSCs through blocking/inhibiting identified regulator(s) using the co-culture system established.

The DPhil project will apply a broad range of cutting edge research techniques covering human cell culture systems, genome-wide, genetic, immunological, proteomic and biochemical methods (3-6). These include 3D cell culture systems of cancer stem cells and immune cells, genome-wide studies (single-cell RNA-seq, ATAC-seq, ChIP-seq) as well as functional studies and mechanistic studies (CyTOF, confocal microscopy, flow cytometry, cell sorting, time-lapse imaging, real-time PCR, western blotting, ELISA, CRISPR/Cas9-mediated gene editing, siRNA gene knockdown).

Collectively, this research will generate data with strong translational relevance, which has the potential to lead to development of therapeutic strategies to target CSCs by small molecule compounds or by cell-based immune therapies.

THEMES

Cancer stem cells
Stem cell biology
T cell immunology
Immunotherapy
Cancer therapy
Pancreatic cancer

THE RESEARCH GROUP

This multidisciplinary project is part of the research programme led by Dr Siim Pauklin and Dr Liye Chen, who are Principal Investigators at the Botnar Research Centre (https://www.ndorms.ox.ac.uk/about/botnar-research-centre), Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (https://www.ndorms.ox.ac.uk/about/botnar-research-centre). The DPhil project aims to develop novel 3D co-culture systems that allow studying the crosstalk between pancreatic cancer stem cells and stromal cells. The student will closely interact with the research groups of Udo Oppermann and Paul Bowness, and other colleagues at the Botnar Research Centre, while also benefitting from the collaborations with researchers at the Kennedy Institute of Rheumatology (https://www.ndorms.ox.ac.uk/about/kennedy-institute-of-rheumatology), the Target Discovery Institute (http://www.tdi.ox.ac.uk/), the CRUK/MRC Oxford Institute for Radiation Oncology (https://www.oncology.ox.ac.uk/about-us), and the Wellcome Trust Centre for Human Genetics (https://www.well.ox.ac.uk/).

For general inquiries: Sam Burnell ([e-mail]), Graduate Studies Officer.

For project related inquiries: Dr Liye Chen ([e-mail]) and Dr Siim Pauklin ([e-mail]), Botnar Research Centre, University of Oxford.

TRAINING

The Botnar Research Centre plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which enables and encourages research and education into the causes of musculoskeletal disease and their treatment. Training will be provided in techniques including state-of-the-art laboratory methods essential for cancer research and the stem cell field.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome. Students will also be required to attend regular seminars within the Department and those relevant in the wider University.

Students will be expected to present data regularly in Departmental seminars, the Pauklin and Chen group and to attend external conferences to present their research globally, with limited financial support from the Department.

Students will also have the opportunity to work closely with the Udo Oppermann and Paul Bowness groups. Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and run by the IT department (information will be provided once accepted to the programme).

HOW TO APPLY

The Department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Graduate Studies Officer, Sam Burnell ([e-mail]), who will be able to advise you of the essential requirements.

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online (https://www.ox.ac.uk/admissions/graduate/applying-to-oxford/application-guide?wssl=1) and the DPhil research will commence in October 2021.

Applications should be made to the following programme using the specified course code:

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford

References

1. French, R., Feng, Y., and Pauklin, S. (2020). Targeting TGFβ signalling in cancer: toward context-specific strategies. Trends in Cancer 7, 538-540.
2. Feng, Y., and Pauklin, S. (2020). Two sides of the same coin: the roles of TGF-β in colorectal carcinogenesis. Gastroenterology 20, 30395-4.
3. Bertero, A., Madrigal, P., Galli, A., Hubner, N.C., Moreno, I., Burks, D., Brown, S., Pedersen, R.A., Gaffney, D., Mendjan, S *., Vallier, L., * Pauklin, S * (2015). Activin/Nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark. Genes Dev 29, 702-717.
4. Pauklin, S., and Vallier, L. (2015). Activin/Nodal signalling in stem cells. Development 142, 607-619.
5. Pauklin, S., Madrigal, P., Bertero, A., and Vallier, L. (2016). Initiation of stem cell differentiation involves cell cycle dependent transcription of developmental genes by Cyclin D. Genes Dev 30(4), 421-33.
6. Pauklin, S., and Vallier, L. (2013). The cell-cycle state of stem cells determines cell fate propensity. Cell 155, 135-147.
7. Hsu, J-M., Xia W., Hsu Y-H., Chan L-C., Yu W-H., Cha J-H., Chen C-T., Liao H-W., Kuo C-W., Khoo K-H., Hsu J.L., Li C-W., Lim S-O., Chang S-S., Chen Y-C., Ren G-X., Hung M-C. (2018). STT3-dependent PD-L1 Accumulation on Cancer Stem Cells Promotes Immune Evasion. Nat Commun. 15;9(1):1908.

英國劍橋大學

The Genetic Analysis of Multiple SclerosisDeadline: December 03, 2020
About the Project

Through genome-wide association studies and related follow up efforts we have identified over 100 genetic variants that influence the risk of developing multiple sclerosis. These variants map almost exclusively to regulatory regions of the genome that are active in immune cells suggesting that these variants primarily exert their effects by altering the expression of otherwise normal genes in critically important immune cell sub-types.
In work already completed we have established that at least two of the associated variants influence the expression of key immune signalling genes in B cell sub-types. These data confirm the importance of B cells in pathogenesis which is in keeping with the latest clinical trial data showing the positive effects of anti-B cell therapies. This project will focus on fine mapping the causal variants underlying observed associations by exploring the expression of key immune genes in B cell subtypes. The work will involve mapping of transcription and chromatin architecture, as well as protein expression and cell function.

The successful student will work closely with colleagues at the McGill University Epigenomics Mapping which is a leading institution in the International Human Epigenome Consortium (IHEC), the project may include the opportunity for willing students to spend a period of their research in Montreal.

Funding Notes

Funding deadline is 3rd December 2020 for start in October 2021. When applying indicate on the application the funding options (GATES USA *deadline 14/10/20*, Gates Cambridge or other Cambridge Funders). Home/EU and International applications are all considered for funding.

英國謝菲爾德大學

Measuring Viscosity and Oil Film Thickness In-Situ in Tribo-Systems

Deadline: 23 Sep 2020

About the Project

We have a vacancy for an enthusiastic and self-motivated PhD student for a joint PhD project between the Leonardo Centre for Tribology at the University of Sheffield and AC2T in Austria.

About the Project

All machines require lubrication to function properly. The thickness and of the oil film that forms in machines like auto-engines, wind turbine transmissions, marine engine propellers, or aero gas turbine bearings are critical to their operation. These oil films are very thin and under conditions of high pressure, temperature, and rate of shearing. The way the oil behaves under these conditions is difficult to predict and we need measurement methods to determine how they perform. This project is about using ultrasound to measure lubricant behaviour in-situ on real machine element contacts.

You will be developing sensors that can be used on test rigs to understand the fundamentals of lubricant behaviour under high pressure and shear, and also as condition monitoring devices to monitor components in the field. The group has a lot of experience working with ultrasound and machine elements and you will be well supported and guided.

You will be developing measurement methods in the Leonardo lab and then implementing these on test machines at AC2T. You will spend most of your time at Sheffield, with frequent meetings and occasional visits to Ac2T. In addition, you will spend a period of 6 – 9 months in Austria at AC2T where you will apply some of your research methods on the tools and equipment at AC2T.

About the Centres

The Leonardo Centre is based in the Department of Mechanical Engineering at the University of Sheffield. It is one of the leading tribology groups in the UK with 6 academic staff and over 50 PhD students. The Centre covers a wide range of fundamental and applied research and as a large group of industrial funders and collaborators. You will be joining a team of helpful and social PhD students working in three well equipped labs.

The Austrian Competence Centre for Tribology, AC2T is Austria’s leading centre of excellence in tribology and acts as an R&D service provider for industrial companies in fields such as smart materials, surfaces and coatings, lubricants and lubrication systems, high-resolution wear measurement systems, simulation and modelling of friction and wear processes.

For further information on the project itself please contact Prof Rob Dwyer-Joyce – [e-mail]

Funding Notes

Requirements:

• 1st or 2:1 degree in Engineering, Materials Science, Physics, Chemistry, Applied Mathematics or other Relevant Discipline.

• The PhD is funded at the standard EPSRC rate covering fees and bursary. Funding is only available to cover the level of fees set for UK applicants for 3.5 years. Applicants from non UK/EU will need to cover the extra fees form their own funds.

英國約克大學

Audio personalisation for Accessible Augmented Reality Narratives (MSc by Research)Deadline: October 05, 2020
About the Project

We are seeking a suitable candidate to conduct a 1 year fully funded MSc by Research on the topic of enhancing accessibility in Augmented Reality experiences through Enhanced Audio Description (EAD). This project is a collaboration between the University of York Department of Electronic Engineering AudioLab (https://audiolab.york.ac.uk/) and BBC Research and Development (https://www.bbc.co.uk/rd), through the XR Stories AHRC Creative Cluster R&D Partnership (https://xrstories.co.uk/).

Audio description (AD) is an accessibility strategy for visually impaired audiences using superimposed third-person narration to describe visual elements. EAD is an alternative approach developed at York, which conveys these visual elements instead through soundtrack enhancement, spatial audio, and first-person character narration. However, the use of EAD within fully immersive XR narrative experiences, which allow six-degrees of freedom interaction, has not been explored.

Of the XR mediums, Augmented Reality (AR); where virtual characters and narrative events unfold in the physical environment of the consumer, presents the largest challenge. As in other mediums, AR accessibility strategies need to ensure the narrative elements are conveyed, but they must also include appropriate navigation cues so that the consumer can explore the story world freely.

The successful candidate will explore this challenge, working with York AudioLab and BBC R&D to build directly on Kearney and Lopez’s EAD research and previous accessible audio work for hard of hearing audiences by Ward and BBC R&D. In this MSc, they will identify a hierarchy of soundtrack elements necessary for personalisation of AR experiences such that both narratively important and navigational cues are preserved. The student will develop a prototype AR narrative experience that will be directly informed by focus groups with visually impaired XR users as well as AR content creators. Participants in these groups will also be asked to rank soundtrack elements on importance for narrative understanding and navigation. The prototype will then be used to develop a narrative and navigational hierarchy of soundtrack elements for the purpose of personalisation.

The successful applicant should have a strong interest in sound and immersive audio technology, as well as a keenness for improving accessibility in media. Experience or interest in subjective experiments or user experience testing, and a basic understanding of statistics would also be beneficial. The successful candidate will study in the Department of Electronic Engineering AudioLab at the University of York supervised by Gavin Kearney and Lauren Ward, and collaborate with Chris Pike at BBC Research and Development.

Candidates must have (or expect to obtain) a minimum of a UK upper second-class honours degree (2.1) or equivalent in Computer Science, Electronic Engineering, Music Technology or a related subject.

This MSc by Research is due to start 1st November 2020.

How to apply:
Applicants must apply via the University’s online application system at https://www.york.ac.uk/study/postgraduate-research/apply/. Please read the application guidance first so that you understand the various steps in the application process. To apply, please select the MSc by Research in Electronic Engineering or Music Technology for October 2020 entry. Please specify in your MSc application that you would like to be considered for this studentship.

The closing date for applications is Monday 5th October 2020. Select candidates will be asked to attend a short interview approximately 1 week after the closing date.

For informal enquires please contact Dr. Gavin Kearney ([e-mail]).

Funding Notes

The studentship will cover the tuition fee at the home/EU rate (£4,407 in 2020/21) and a stipend at the standard research council rate for one year (£15,285 in 2020/21). International (non-EU) candidates are also welcome to apply but will be required to pay the difference between the UK/EU and international tuition fee rates (approximately £17,000 for the duration of the programme).

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