The epigenomic, transcriptional and diagnostic architecture of neurodevelopmental disorders caused by exposure to maternal infection

About the Project

A fundamental unknown in understanding mechanisms of disease, and therefore improving therapy, is how stressors experienced during critical developmental periods influence the genesis or ‘programming’ of adult disease (Estes & McAllister 2016). In particular, stressors experienced during pregnancy may increase the likelihood of offspring developing cognitive disorders across their lifespan (Knuesel et al. 2014). Whether this is due to changes directly affecting brain development in utero, altered maternal behaviour, adolescent brain development or a combination of these, is unclear, and the mechanistic pathways underpinning affected traits remain poorly defined.

Maternal stressors result in epigenetic modifications in placental tissue and offspring brain, and are likely to be key candidate mechanisms leading to altered gene expression and thus developmental changes in the brain resulting in cognitive and behavioural disturbances (Woods et al. 2021).

The placenta plays a crucial role in maternal-fetal interactions. Modulation of fetal adaptive responses may lead to an increased susceptibility to development of neuropsychiatric disease later in life. Placental development is affected by maternal stressors, but how this links to cognitive impairment in offspring is unclear. We have recently established a link between reduced placenta weight, dysfunctional amino acid transport and increased risk for schizophrenia (Kowash et al. 2022). We propose that epigenetic mechanisms mediate the effects of maternal stressors on placental function leading to altered brain development and later impaired cognitive development.

The proposed project capitalizes on our recently established neurodevelopmental rat model of maternal immune activation (Murray et al. 2019, Kowash et al. 2022, Potter et al. 2023), seeking to investigate both prenatal effects of maternal immune activation on placental function and adult behavioural phenotypes linked to schizophrenia development. We will use multidisciplinary approaches to map functional changes along a developmental timeline that links placental functional development with fetal brain development and adolescent environmental conditions to offspring behavioural traits. Evaluation of placental development and function, molecular array studies, epigenomic, histological and functional analyses in brain together with behavioural interactions, cognitive and behavioural analyses in our rodent neurodevelopmental model will be conducted. The project offers broad scientific training covering mammalian disease and behavioural research, histology, physiology, molecular biology, epigenetic and gene expression analyses. This multidisciplinary project will suit candidates who wish to apply their skills to a significant research question using cutting-edge technologies.

Eligibility

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline.

How to Apply

To be considered for this project you MUST submit a formal online application form – on the application form select PhD Neuroscience Programme. Full details on how to apply can be found on the Website.

If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk