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  Mechanistic analysis of neurodevelopmental disorders caused by mutations in the gene RAC1


   Faculty of Biology, Medicine and Health

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  Dr T Millard, Dr S Banka  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

RAC1 is a signalling protein that regulates many cellular processes and is essential during embryonic development. We recently discovered a novel genetic disease called RAC1-related neurodevelopmental disorder (RAC1-NDD) that results from mutations in the RAC1 gene. Individuals with this condition have a variety of neurological abnormalities, but the nature of abnormalities differ between individuals with different mutations. This project will explore the molecular and cellular mechanisms by which the RAC1 mutations identified in patients give rise to neurological abnormalities and why different mutations in the RAC1 gene result in different abnormalities. This will be done using a combination of cell culture and model organism approaches. Cell culture will be used to explore how different RAC1 mutations affect cell morphology and behaviour. The fruit fly Drosophila will be used as a simple animal model to investigate how RAC1 mutations affect neuronal development and function. In addition, computational bioinformatic approaches will be used to identify and characterise novel disease mutations in RAC1 and related genes.

This is a truly inter-disciplinary project led by a basic scientist and a clinical academic who will bring complementary areas of expertise. The project will equip the student with a range of versatile skills including bioinformatic analysis of human genome/exome sequences, cell culture, modelling human disease in model organisms and cloning/transgenesis techniques such as CRISPR. The skills and knowledge provided by project will provide a solid foundation for a future career in disease-gene discovery, precision medicine, translational medicine or neuroscience.

Eligibility 

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in biological or medical science or a relevant subject area. Applicants with interests in using model organism and cell culture approaches to understand human disease are encouraged to apply.

Before you Apply 

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.  

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 - PhD Neuroscience.

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. For more information please visit https://www.bmh.manchester.ac.uk/study/research/international-phd/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]  

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/  

Biological Sciences (4)

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/

References

Banka S, Bennington A, Baker MJ, Rijckmans E, Clemente GD, Ansor NM, Sito H, Prasad P, Anyane-Yeboa K, Badalato L, Dimitrov B, Fitzpatrick D, Hurst ACE, Jansen AC, Kelly MA, Krantz I, Rieubland C, Ross M, Rudy NL, Sanz J, Stouffs K, Xu ZL, Malliri A, Kazanietz MG, Millard TH. Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology. Brain (2022) 145, 4232-4245. doi: 10.1093/brain/awac049. PMID: 35139179
Reijnders MRF, Ansor NM, Kousi M, Yue WW, Tan PL, Clarkson K, Clayton-Smith J, Corning K, Jones JR, Lam WWK, Mancini GMS, Marcelis C, Mohammed S, Pfundt R, Roifman M, Cohn R, Chitayat D; Deciphering Developmental Disorders Study, Millard TH, Katsanis N, Brunner HG, Banka S. RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes. Am. J. Hum. Genet. (2017) 101 466-477.
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