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KESS2 East PhD in Medicine: Exploring a genetically targeted therapeutic approach for adenomatous polyposis syndromes in 3D organoid cell models


Project Description

In collaboration with the Wales Gene Park (WGP) and our partner company Cellesce, this studentship will exploit existing organoid resources within the Inherited Tumour Syndromes Research (ITSR) Group in addition to establishing, characterising and expanding new lines from material obtained by the ITSR group during the course of the study.

This will result in the development of extensively profiled 3D organoid lines which have been grown in sufficiently abundant quantities from patient material and are representative of the tissues from which they originate.

Background
The genetic syndromes Familial Adenomatous Polyposis (FAP) and MUTYH-associated polyposis (MAP) predispose to a near 100% lifetime risk of colorectal cancer development.

With improved prophylactic surgery for colorectal disease, duodenal disease (adenomas and cancer) is becoming the most common extracolonic manifestation and is a significant cause of morbidity and mortality in these patients.

The current standard of care for patients with FAP and MAP involves radical total colectomy followed by regular upper gastrointestinal surveys of the duodenum. Treatment regimens and their efficacy is varied and is dependent on the disease stage, grade and additional clinical factors.

Importantly, there are high costs associated with the use of regular surveillance intervals to manage the disease effectively. Moreover, very little is known about the natural history or genetic causes of duodenal disease in these syndromes.

Organoid 3D cultures are miniaturised versions of the organs from which they were originally derived. Intestinal organoids contain all of the differentiated epithelial cell types found in the original organ and are able to recreate the spatial organisation of the original tissue.

Organoids can now be produced for multiple organs and are commonly used as a platform for modelling drug responses and investigating mechanisms of disease. Organoid cultures represent an excellent opportunity as pre-clinical models of early colorectal and duodenal tumorigenesis in FAP and MAP patients.

The models which this studentship proposes to develop would allow for targeting of known and putative tumour drivers through processes such as genomic editing (ie CRISPR) to investigate the underlying mechanisms of tumorigenesis in these conditions.

Moreover, the identification of putative therapeutic targets which may arise from this work, are expected to lead towards the development of compounds capable of preventing tumour development in these patients.

Project aims and methods
Use of innovative technology in Wales to generate a novel model of disease
In order to establish new treatments and/or diagnostic methods that can be used in the clinic, evidence from pre-clinical work is needed. Appropriate models of disease are essential tools which are required to support pre-clinical work.

The proposed project would combine two cutting edge technologies, organoid models and CRISPR/Cas9, to develop exciting new opportunities to study human diseases in vitro using more clinically relevant systems.

Elucidation of mechanisms of disease and potential drug targets for therapy
The proposed study will utilise organoid models to look at these identified drivers in vitro. By better profiling the underlying causes of adenoma growth, we can understand the dysregulated pathways that are contributing to polyp formation and determine important targets for drug treatments.

It is expected that this work will have an impact on patients and their at-risk relatives by providing a better understanding of disease. This may lead to improved management of these patients and surveillance recommendations for upper GI disease, in addition to future new treatments and surgical strategies.

Overall, the results may lead to a reduction in bowel cancer in this high-risk group of patients.

Funding Notes

Full UK/EU tuition fees
Doctoral stipend matching UK Research Council National Minimum

Eligibility criteria - Residency
Applicants for these awards must have a home or work address in the East area* of Wales at the time of their application for funding and enrolment.
Eligibility Criteria - Academic
Applicants should possess a minimum of an upper second class Honours degree, master's degree, or equivalent in a relevant subject.
Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS)

References

Applicants must:
have the right to work in the UK on completion of the scholarship
be classified as a ‘home’ or ‘EU’ student
satisfy the respective admissions criteria
It is a condition of eligibility for KESS2 funding that you have not applied for, nor are intending to apply for, a doctoral or research master's loan. Please read clause (3) (m) of The Education (Postgraduate Doctoral Degree Loans) (Wales) Regulations 2018 for more information.

*The East Wales region is comprised of 7 local authorities: Cardiff, Flintshire, Monmouthshire, Newport, Powys, Vale of Glamorgan and Wrexham.

In order to be considered you must submit a formal application via Cardiff University’s online application service. (To access the system click 'Apply Online' at the bottom of this advert)
There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (July 2019). This will take you to the application portal.
If deemed suitable for the project, applicants will be invited to complete a ‘KESS2 Participant Form’ which assesses eligibility for funding. Applicants must also be able to provide supporting documentary evidence of their eligibility. Guidance on this requirement is outlined in the KESS2 Participant Form, an example of which can be downloaded as above. Suitable applicants will be sent this form to complete following the School selection process. Further advice is available from the KESS2 team.

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