Errors that occur during cardiac development cause congenital heart defects (CHD). Despite the prevalence of CHD, the developmental processes that ensure the heart forms correctly are still being elucidated. We will contribute to the understanding of cardiac development by investigating the function of the spliceosome gene Prpf8, and its links to cilia function, during embryonic heart development. A loss of PRPF8 causes reduced cilia motility at the embryonic node, resulting in errors in the left-right specification of the heart. Additional cardiac morphological defects are present in Prpf8 mutants, consistent with abnormalities in cardiac primary cilia. The abnormal function of cardiac primary cilia has been linked to disruptions in a variety of cardiac developmental processes, including altered cell proliferation and abnormal cardiac morphology. In this project we will determine how PRPF8 dysfunction results in aberrant cardiac development, revealing developmental pathways critical for heart formation, which are likely to be disrupted in human CHD patients.
The function of PRPF8 during cardiac development is of particular interest because PRPF8 mutations have direct associations with human congenital heart defects. The discovery of deleterious variants in PRPF8 in CHD patients suggests a requirement for PRPF8 in human cardiac development. The CHD variants may disrupt PRPF8 function in the spliceosome or cilium resulting in errors in heart formation. The precise mechanisms by which PRPF8 mutations affect cardiac development are yet unknown, and we propose to investigate links between PRPF8 function, cilia, and cardiac disease within this project.
Training/techniques to be provided:
Training in developmental biology techniques such as histology, immunohistochemistry and immunofluorescence, in situ hybridisation, and mouse embryo dissection will be provided. Training in standard molecular biology techniques such as PCR, DNA sequencing, and expression analysis will also be provided. In addition to wet lab skills, the student will gain an understanding of the use of informatics databases such as the genome browser and mutation prediction software as part of the project.
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in developmental biology or genetics are encouraged to apply.
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.
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.
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