Maternal diabetes is a major risk factor for fetal overgrowth, which is associated with poor outcomes including stillbirth, neonatal morbidity and increased risk of diabetes in adulthood.
We hypothesise that fetal overgrowth is the consequence of dysregulated placental development/function caused by high maternal glucose levels. Little is known about mechanisms linking abnormal glucose availability and altered placental function. In other glucose-sensing tissues, flux through the hexosamine biosynthetic pathway (HBP), and consequent modification of proteins with O-linked β-N-acetylglucosamine (O-GlcNAc), regulates cellular function. We have shown that the HBP operates in placenta and that proteins in placentas from women with diabetes are differentially modified, leading to alterations in a fundamental cellular process – clathrin-mediated endocytosis (CME).
We now hypothesise that the changes to protein O-GlcNAcylation and consequently, clathrin-mediated endocytosis, caused by maternal diabetes contribute to dysregulated placental development/function and abnormal fetal growth. We therefore propose a functional analysis of altered O-GlcNAc cycling in trophoblast to identify the molecular pathways linking glucose metabolism to adverse pregnancy outcomes. Our approach starts from an investigation of HBP and protein O-GlcNAcylation in healthy tissue and progresses to validation of key findings in term placentas obtained from women with diabetes
Specifically, this project aims to:
1. Establish the effect of altered O-GlcNAcylation on CME regulation of placental development and function by (a) manipulating intracellular O-GlcNAc cycling and (b) mimicking glucose levels and treatment regimens observed in women with diabetes.
2. Assess CME and its downstream consequences in placentas from women with type 1 or type 2 diabetes.
The findings will contribute to our understanding of the fundamental mechanisms governing nutrient transporter activity, how the placenta senses and adapts to maternal nutrient availability and how these processes are affected by maternal diabetes or its treatment. This will provide affected mothers with further information about the consequences of their condition, and, possibly, a further impetus to tightly manage their circulating glucose levels. Moreover, the data generated will underpin the development of interventions – dietary and/or pharmacological (e.g., drugs to regulate protein trafficking and fate) - ¬to optimise placental adaptation to the maternal environment and thereby protect the fetus from the adverse health trajectory initiated by exposure to over-nutrition in early life. The incidence of pregnancy complicated by maternal diabetes is increasing; identifying pathways that might lead to interventions that halt transmission of the disease to the next generation is now essential.
Training/techniques to be provided:
This project will bring together a multidisciplinary group of supervisors with complementary expertise in placental biology, post-translational modification of proteins and the management of pregnant women with diabetes. Our Centre is located in St. Mary’s Hospital, a tertiary referral women’s hospital (8000 deliveries pa). 80+ scientists and clinicians occupy bespoke laboratories and a co-located suite for research clinics. The latter includes a Diabetes in Pregnancy clinic and Placenta Clinic; these facilitate recruitment and provide the setting for research studies. We also benefit from the University’s extensive core facilities for bioimaging, histology, informatics and flow cytometry needed for this 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 previous laboratory experience, particularly in cell culture and molecular biology, are particularly 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 PhD 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.
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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 www.internationalphd.manchester.ac.uk