School of Medicine Projects MRC IMPACT Doctoral Training Partnership
University of Nottingham

School of Medicine Projects MRC IMPACT Doctoral Training Partnership

United Kingdom 02 Mar 2021

ABOUT THE INSTITUTION

جامعة نوتنغهام هي جامعة أبحاث عامة في مدينة نوتنغهام في المملكة المتحدة. تم تأسيسها كجامعة وكلية في عام 1881، ومُنحت الميثاق الملكي في عام 1948. تمتلك الجامعة فروعًا أخرى لها خارج المملكة المتحدة، فل

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OPPORTUNITY DETAILS

State University
Area
Host Country
Deadline
02 Mar 2021
Study level
Opportunity type
PhD
Specialities
Eligible Countries
This opportunity is destined for all countries
Eligible Region
All Regions

Reference MED1582

Closing Date Tuesday, 2nd March 2021

Department Medicine

Applications are open for a range of exciting projects around the theme of complex disease.

These 42-month PhD studentships, starting in October 2021, are offered through IMPACT – a doctoral training partnership between the Universities of Birmingham, Leicester and Nottingham. The University of Nottingham is advertising 8 projects in order to recruit to 4 studentships (2 IMPACT and 2 iCASE) in total.

You will study alongside other PhD students across a diverse range of projects, enabling you to think creatively and perform innovative, world- leading research. You will also benefit from the expertise of our research partner, the Research Complex at Harwell.

Applications will close at 5.00 pm on 7 January 2021. Funding is provided by the Medical Research Council. Please ensure that your application is submitted with all required documentation as incomplete applications will not be considered.

Full information about the eligibility criteria and application process are on the MRC IMPACT DTP website.

The following IMPACT projects are available in the School of Medicine:

Profiling delivery of therapeutics to malignant brain tumours through multimodal analytics and imaging - Peter Harvey

Most chemotherapeutics fail in development, but we often only have survival rates as a readout of whether the drug worked. Nowhere is this limitation more prevalent than in the brain. In order to improve the drug development pipeline and increase our understanding of how drugs work and interact with tumours, we need new methods of analyses. The project will use multiple, complementary techniques in order to visualise brain tumour drugs in a new light:

MRI: magnetic resonance imaging using carefully designed MRI-active chemotherapeutics will allow real-time tracking of drugs in vivo

Microscopy: fluorescence microscopy and immunohistochemistry to understand molecular details and track drugs in vitro at the sub-cellular level

Mass spectrometry: cutting edge mass spec techniques to map drugs in ex vivo tissue at cellular resolution and to analyse the tumour microenvironment through protein profiling.

There is extensive opportunity to develop broad interdisciplinary skills, with training in chemical synthesis, in vitro culture, small animal surgery, MRI data acquisition, and mass spectrometry.

These techniques will be applied to the same tissue samples taken after in vivo imaging, with co-registration of serial samples to build a data portfolio of drug delivery, effect, and tumour microenvironment, and ultimately improve clinical outcomes. 

Novel in vitro, in silico and in vivo insights into hydrodynamic and motor function of the colon in complex functional gastrointestinal diseases - Luca Marciani

This project builds on a recent collaboration between Nottingham (Medicine and Physics) and Birmingham (Chemical Engineering) using magnetic resonance imaging (MRI), a novel biomechanical computer-controlled bench model of the human proximal colon that can simulate colon motility patterns, and hydrodynamic computer modelling to investigate human colon function in health and in complex gastrointestinal diseases affecting luminal motor, secretory and transport function.

The underlying hypotheses are that the in vitro and in silico models of the human colon will enable the development and validation of MRI methods to quantitate hydrodynamic and motor function and, in turn, that MRI will provide unique data to the bench and computer models of the colon making them more in vivo relevant.

This work will have impact on our understanding of colonic functional disease, MRI imaging methodology and pharmaceutical sciences.

The PhD student will be hosted in Nottingham and will work across world leading MRI and engineering teams, with support from a pharmaceutical company gaining multidisciplinary transferrable skills encompassing image data analysis, computation, mathematics, modelling of physiological hydrodynamic and motor function and whole organ physiology and colonic factors in drug dissolution.

iCASE:

Unravelling drug-gene-phenotype interactions in complex cardiovascular diseases - Chris Denning, with Davor Pavlovic (Birmingham) and AstraZeneka (non-SME)

Globally, cardiovascular disease is the leading cause of death, with underlying genetic mutations, co-morbidities and drug-induced off-target cardiotoxicity being especially troublesome. Inappropriate testing models belie these issues. The top 200 drugs account for 66.6% of the 4.3bn prescriptions in the USA/pa. Yet, 81 are black boxed, 82 carry cardiovascular adverse drug reaction warnings and 1 in 7 licensed drugs deemed efficacious in phase III trials are withdrawn from the market. 

This collaborative project partners the Universities of Nottingham and Birmingham with AstraZeneca. All have experience in technologies spanning human induced pluripotent stem cells (hiPSCs), differentiation to cardiovascular linages, molecular/functional phenotyping, pharmacology and transcriptomics. Our published work pioneered CRISPR gene editing in hiPSC to create variants that cause hypertrophic cardiomyopathy (HCM), a complex, heterogeneous disease that associates with considerable morbidity and mortality.

Diverse skillsets and training will be combined to complete 3 objectives, aimed at future tailoring drug therapy to patient genetics: 

Are different AP-1 subunit heterodimers associated with colorectal cancer patient outcome, metastasis and tumour hypoxia? - Alan McIntyre with Fastbase Solutions UK (SME)

Colorectal cancer is the third most common cancer leading to 500,000 deaths a year worldwide. Colorectal cancers frequently contain regions of low oxygen (hypoxia). Tumour hypoxia is caused by high proliferative rates and poor vascularisation. Tumour hypoxia is associated with therapy resistance, increased metastasis and worse patient survival. Identifying novel approaches to target hypoxic tumours is key to improving patient survival. 

We recently identified that AP-1 is a major regulator of hypoxic tumour survival and growth. AP-1 is a transcription factor formed by the heterodimerisation of FOS and JUN protein subunits. The function of these heterodimers is not interchangeable and target genes of the AP-1 heterodimers differ. AP-1 target genes regulate major hallmarks of cancer phenotypes. In this project we aim to quantify AP-1 heterodimer levels using a novel imaging approach that allows functional characterisation of protein states in patient tumour samples. We will identify which AP-1 heterodimers are associated with colorectal tumour hypoxia, metastasis and patient survival. 

We will also investigate the functional role of clinically relevant AP-1 subunits. We will use CRISPR CAS9 gene knockouts of AP-1 subunits in colorectal cancer cell lines and investigate cancer phenotypes including 3-Dimensional growth and tumour invasion.

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