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(MRC DTP) RAC1 mutations in human neurodevelopmental syndrome: from mechanism to treatment

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  • Full or part time
    Dr T Millard
    Dr S Banka
    Dr S Woolner
    Prof V Allan
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

RAC1 regulates a variety of essential cellular functions1,2,3. We recently showed that it is critical for normal human development by discovering a novel neurodevelopmental syndrome caused by mutations in the RAC1 gene4. Very interestingly, our subsequent unpublished work has identified a treatment target that can be used to correct the neuronal defects. The principle aims of this project are to -
1. Expand the cohort of patients with this syndrome
2. Understand the molecular and cellular mechanisms by which different RAC1 mutations lead to abnormal neuronal development and function
3. Devise strategies for future treatments.

Experimentally, the project will involve -
1. Computational bioinformatics analysis to identify and classify new patients with RAC1 mutations.
2. Cell culture and biochemistry experiments to study how the mutations found in patients affect the molecular characteristics and cellular functions of RAC1.
3. Modelling the effect of RAC1 disease mutations on neurodevelopment in Drosophila (fruit fly) and Xenopus (frog) model organisms.
4. Drug screening in cultured cells to identify potential treatments for this condition.

This is a truly inter-disciplinary project led by a team composed of basic scientists and a clinical academic who will bring complementary areas of expertise. Each of the supervisors have active research programmes and 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 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.

https://www.research.manchester.ac.uk/portal/tom.millard.html
https://www.research.manchester.ac.uk/portal/siddharth.banka.html
https://www.research.manchester.ac.uk/portal/sarah.woolner.html
https://www.research.manchester.ac.uk/portal/viki.allan.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 www.manchester.ac.uk/mrcdtpstudentships

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. Duquette, P. M. & Lamarche-Vane, N. Rho GTPases in embryonic development. Small GTPases 5 e972857 (2014).
2. Ng, J. et al. Rac GTPases control axon growth, guidance and branching. Nature 416 442–447 (2002).
3. Woolner S, Jacinto A, Martin P. The small GTPase Rac plays multiple roles in epithelial sheet fusion--dynamic studies of Drosophila dorsal closure. Dev Biol. 282 163-73. (2005)
4. 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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