Understanding the genetic pathways required during development is a fundamental step in discovering how alterations in those pathways can cause developmental malformations leading to birth defects. A signalling pathway of interest during mammalian development is the Slit:Robo pathway. This pathway has been characterised predominantly for its requirements during nervous system development. However, recent studies have shown that this pathway is also critical for cardiac development. Mutations in Slit3 cause structural abnormalities in the heart, altering the formation of the ventricular and atrial septa. We therefore propose to investigate the developmental functions of Slit3, and determine how loss of Slit3 function causes malformations of the heart during gestation, as a model for exploring requirements for Slit:Robo signalling in mammalian organ development. Slit proteins are ligands for Robo receptors. Many questions remain unanswered regarding the interactions between these proteins and pathway activation. For example, Slit ligands contain a cleavage site, but the prevalence of cleavage during development and its effect on pathway signalling in the heart is unknown. We propose to gain a deeper understanding of Slit:Robo signalling by investigating the function of the Slit3 ligand during cardiac development. We are well-placed to investigate Slit3 function during development, because we have two Slit3 mutant mouse lines that are ideal model systems for the evaluation of the requirements for Slit3 during gestation. We have found that both these Slit3 mutant lines display cardiac septal defects during development. Detailed characterisation of heart development in these mutant mouse models, and comparison to wild type controls, will form a substantial part of the project. Additionally, we will incorporate the use of bioinformatics methods to interrogate large datasets examining human sequence variation to formulate a better understanding of how alterations in SLIT3 sequence affect protein function and pathway activation. Combined, these approaches will provide insights into the requirements for Slit3 during development and the malformations that arise when Slit3 function is disrupted.
https://www.research.manchester.ac.uk/portal/kathryn.hentges.htm
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.
Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships
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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