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(MRC DTP) Understanding the mechanism and finding treatment of neurodevelopmental disorder caused by KMT2C mutations


Project Description

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.

https://www.research.manchester.ac.uk/portal/siddharth.banka.html
https://www.research.manchester.ac.uk/portal/andrew.d.sharrocks.html
https://www.research.manchester.ac.uk/portal/sue.kimber.html
https://www.research.manchester.ac.uk/portal/adam.stevens.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Faundes, V. et al. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders. The American Journal of Human Genetics 102, 175–187 (2018).
2. Bjornsson, H. T. et al. Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome. Science Translational Medicine 6, 256ra135-256ra135 (2014).
3. Benjamin, J. S. et al. A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome. PNAS 114, 125–130 (2017).
4. Tsai, I.-C. et al. Small molecule inhibition of RAS/MAPK signaling ameliorates developmental pathologies of Kabuki Syndrome. Scientific Reports 8, 10779 (2018).

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