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MRC DTP: Exploring the integrin-Rac1 pathway to understand and treat neurodevelopmental disorders

Posted by , on 9 November 2021

Closing Date: 12 November 2021

How to apply: https://www.bmh.manchester.ac.uk/study/research/mrc-dtp/apply/

  • Application deadline: 12 November 2021
  • Interviews: week commencing 10 January 2022 

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Faculty of Biology, Medicine and Health, The University of Manchester

PhD Research Project Competition Funded Students Worldwide

Martin Humphries

Andreas Prokop

Sid Banka

Tom Millard

Details

Background: We discovered that integrins and Rac1, form a pathway essential for axon growth during normal nervous system development. Axon growth establishes connections between neurons across the nervous system, essential for normal cognitive function.  Accordingly, integrin mutations cause intellectual disability in mouse and humans [1,2], and we discovered that germline RAC1 mutations cause a human genetic disorder likewise characterised by intellectual disability [3].

Aims: In this project the student will identify further components of the integrin-Rac1 pathway involved in axonal growth, establish their potential disease links and test therapeutic strategies.

Methods:  

(a)  The student will identify further axon growth-relevant components of the integrin-Rac1 pathway using mass-spectrometry experiments and their bioinformatic analysis.

(b)  Candidate proteins will be experimentally assessed in neuronal cell culture and in vivo to assess whether and how they function within the integrin-Rac1 pathway; this will involve extracellular matrix extraction, primary neuron cultures, brain dissections, Drosophila genetics and advanced imaging.

(c)  The student will identify disease-relevant mutations in integrin-Rac1 pathway components through interrogating large human genomic datasets via computational bioinformatics analysis and clinical correlation.

(d)  Through in vivo studies, the student will establish whether/how candidate proteins impact on axon growth leading to miswiring as a cause for intellectual disability.

(e)  The student will have the opportunity to test approved drugs to assess potential ameliorating effects on aberrant axon growth caused by these mutations.

Training: The experimental approaches used are highly inter-disciplinary and will equip the student with a wide range of skills relevant for the biomedical sciences. To guarantee high quality training and optimal progress, the project will be supervised by experts in the field. Martin Humphries is an expert on integrins and the mass-spectrometry analysis of integrin complexes [4]. Andreas Prokop has 30 years experience of applying genetics, cell biology and imaging approaches to study the Drosophila nervous system, integrins and the cytoskeleton [5], and is also an expert in science communication (https://poppi62.wordpress.com/publications); he has established the cellular model used here. Siddharth Banka is an expert in human genetics, analysis of the human genome and has discovered more than 20 novel human disorders [3]. Tom Millard is highly experienced with Drosophila genetics, molecular cloning and imaging and has established a set of disease-relevant Rac1 mutations available for this project [3].  

Entry Requirements

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 an appropriate area of science, engineering or technology.

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

Funding Notes

Funding will cover UK tuition fee and stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

[1] Schuch et al., 2014, Gene 553, 24ff. — https://doi.org/10.1016/j.gene.2014.09.058
[2] Ellegood et al., 2012, Front Psychiatry 3, 10.3389/fpsyt.2012.00037ff. — https://doi.org/10.3389/fpsyt.2012.00037
[3] Reijnders et al., 2017, Am J Hum Genet 101, 466ff. — https://doi.org/10.1016/j.ajhg.2017.08.007
[4] Chastney et al., 2020, J Cell Biol 219, ff. — https://doi.org/10.1083/jcb.202003038
[5] Qu et al., 2019, eLife 8, e50319ff. — https://doi.org/10.7554/eLife.50319




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