Background: We recently identified a novel human syndrome caused by mutations in a gene called KMT2C1. Patients with this condition predominantly have developmental delay and intellectual disability indicating the important function of this gene in brain’s normal development and function. However, the role of KMT2C in human neurodevelopment is poorly understood. We know that KMT2C is required for laying down critical epigenetic marks in cells and that abnormalities in such marks can be corrected by drugs 2–4.
Project: In year 1 we will generate induced pluripotent stem cells (iPSCs) through patient samples and state-of-the-art technologies such as the CRISPR-Cas9 system. We will differentiate the disease and control iPSCs into cortical neurons and study their characteristics in detail. Dr Banka led the identification of the KMT2C-disorder, has a large cohort of patients with this new condition and has previously used CRISPR-Cas9 to study mechanisms of several genetic conditions. Prof Kimber is an expert in using and differentiating stem cells for understanding human diseases.
In year 2 we will employ advanced techniques such as single-cell ATAC-Seq, bulk RNA-Seq and ChIP-Seq at different stages of differentiation to understand the mechanisms behind the abnormalities observed in the iPSC-derived neurons. Prof Sharrocks is an epigenomics expert and routinely uses such techniques in the context of human diseases. We will use advanced systems biology approaches for multi-omics data integration. Dr Stevens has extensive experience in using both data-driven and hypothesis-free approaches for analysis of multi-omics data.
In the final year we will test a selection of drugs to attempt phenotype rescue in our cell models.
Outcome: The project will lead to identification of mechanism underlying a novel human neurodevelopmental syndrome and pave the way to possible future clinical trials.
The student will benefit from being supervised by an inter-disciplinary team of basic scientists and a clinical academic with complementary areas of expertise. This will expose the student to a breadth and depth of biomedical research that is usually very difficult to find in a project set in a single laboratory.
The skills learnt in the project are likely to be in high demand for several years in biological and medical sciences. The project will provide a solid foundation in understanding disease mechanisms and development of new treatments.
Entry Requirements
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a relevant area / subject. Candidates with experience in working with stem cells or CRISPR-Cas9 with an interest in using large datasets to study rare diseases are encouraged to apply.
How To Apply
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title.
For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/”
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