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


   Faculty of Biology, Medicine and Health

  , ,  Applications accepted all year round  Self-Funded PhD Students Only

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 First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a biological discipline including Biology, Neuroscience and allied fields, Pharmacology, Molecular Biology. Applicants with experience in basic molecular techniques and an interest in neurodevelopment are encouraged to apply.

Before you Apply 

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.  

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 - PhD Neuroscience.

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 https://www.bmh.manchester.ac.uk/study/research/international-phd/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team   

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/  

Biological Sciences (4) Medicine (26)

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website View Website

References

Estes ML, McAllister AK. (2016). Maternal immune activation: Implications for neuropsychiatric disorders. Science 353(6301):772-777.
Kowash H, Potter HG, Woods RW, Ashton N, Hager R, Neill JN, Glazier JD. 2022. Maternal immune activation in rats induces dysfunction of placental leucine transport and alters fetal brain growth. Clinical Science 136:1117-1137.
Knuesel L, Chica L, Britschgi M, Schobel SA, Bodmer M, Hellings JA, Toovey S, Prinssen EP. (2014). Maternal immune activation and abnormal brain development across CNS disorders. Nature Reviews Neurology 10:643-646.
Murray KN, Edye ME, Manca M, Vernon AC, Oladipo JC, Fasolino V, Harte MK, Mason V, Grayson B, McHugh PC, Knuesel I, Prinssen EP, Hager R, Neill JC. 2019. Evolution of a maternal immune (mIA) model in rats: early developmental effects. Brain, Behavior, and Immunity 75:48-59.
Potter HG, Kowash HM, Woods RM, Revil G, Grime A, Deeney B, Burgess MA, Aarons T, Glazier JD, Neill JC, Hager R. 2023. Maternal behaviours and adult offspring behavioural deficits are predicted by maternal TNFα concentration in a rat model of neurodevelopmental disorders. Brain, Behaviour, and Immunity 108:162-175
Woods RM, Lorusso JM, Potter HG, Neill JC, Glazier JD, Hager R. 2021. Maternal immune activation in rodent models: a systematic review of neurodevelopmental changes in genes expression and epigenetic modulation in the offspring brain. Neuroscience and Biobehavioral Reviews 129:389-421.
Ursini G, Punzi G, et al. (2018). Convergence of placenta biology and genetic risk for schizophrenia. Nature Medicine 24:792-801.

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