Translation of mRNA into proteins is a critical cellular biological process. We recently described a novel human disorder, now called Faundes-Banka Syndrome (FABAS), caused by heterozygous variants in EIF5A1 that encodes a translation factor. FABAS is characterised by developmental delay, small head size and craniofacial defects (https://www.nature.com/articles/s41467-021-21053-2). Using yeast and zebrafish model systems we showed that these variants impair eIF5A function and that the phenotypes in the model systems can be rescued by food supplement (spermidine) that may be a potential treatment for this disease. Further to our initial publication, we have now also identified additional patients that has expanded the genetic and clinical spectrum of the disorder. We have also developed a zebrafish model with stable germline eif5a mutation that we are using to study the function of the gene in neurodevelopment.
The overall aim of this project is to improve diagnosis, mechanistic understanding, and treatment of monogenic disorders caused by defects in eif5a and related components of the protein synthesis machinery. This aim will be achieved by the following objectives -
1. Studying and expanding the clinical and genetic spectrum of these disorder through clinical and bioinformatic studies.
2. Investigate functional impact of selected variants by developing a whole animal model (zebrafish), using CRISPR, combined with neurodevelopmental phenotypic and biochemical characterisation via fluorescent microscopy, RNA-seq, mass spectrometry and biochemical assays of global and specific protein synthesis functions.
3. Investigate treatment in neurodevelopmental disease zebrafish models caused by variants in protein synthesis genes using pharmacological and genetic approaches.
Outcome:
The student will contribute to providing novel insights into a human disorder at the interface of fundamental biology and translational precision medicine. The student will learn fundamental interdisciplinary and quantitative skills, as well as gaining significant experience of studying whole organism physiology in context of human disease.
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 a relevant subject area. Applicants with experience in zebrafish modelling or with an interest in neurodevelopmental disease and genetics 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 Medical Genetics.
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 FBMH.doctoralacademy.admissions@manchester.ac.uk
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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