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Epigenetic mechanisms of behavioural, placental and cognitive impairment in a neurodevelopmental model for schizophrenia


Project Description

A fundamental question in disease research 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 have effects on the propensity to develop cognitive disorders in the offspring (Knuessel et al. 2014). Whether this relates to changes directly affecting brain development in utero, or altered maternal behaviour, or a combination of these, is unclear. Further, the mechanisms underlying such effects remain poorly defined. The placenta plays a crucial role in maternal-fetal interactions and the modulation of fetal adaptive responses may lead to increased propensity to disease development later in life. Placental development is affected by maternal stressors, but how this links to cognitive impairment in offspring is unclear. Recent genome-wide association studies have identified risk factor genes for schizophrenia which adversely affect placentation (Ursini et al. 2017). This may explain the high level of early life complications in patients who later develop schizophrenia and male susceptibility.

Maternal stressors result in epigenetic modifications (DNA methylation and histone modifications) in offspring brain and placenta and are likely to be key candidate mechanisms leading to altered gene expression and thus developmental changes in the brain resulting in cognitive impairment (Akbarian 2014). The proposed project seeks to investigate genome-environment interactions at the epigenetic level that link to schizophrenia development. We will use a multidisciplinary approach to map functional changes along a developmental timeline that links placental morphological development to offspring behavioural traits. Evaluation of placental morphological development, molecular array studies, epigenomic and histological analyses in brain and placenta together with parent-offspring behavioural interactions, cognitive and behavioural analyses in a rodent neurodevelopmental model of schizophrenia will be conducted. The project therefore offers broad scientific training covering mammalian disease and behavioural research, histology, physiology, molecular biology, epigenetics and gene expression.

Training/techniques to be provided:

The student will be trained in core biological and molecular skills ranging from experimental design, in-vivo techniques including detailed behavioural analysis, histology to statistical analysis as well as the emerging field of epigenetics. This project offers the unique opportunity to work at the forefront of epigenetics research linked to major disease challenges, which are core areas identified by research councils in the UK (BBSRC, MRC) and the US (NIH).

Funding Notes

Candidates are expected to have at least a 2:1 or equivalent foreign degree classification in a biological discipline including Biology, Biomedical Sciences, Molecular Biology, Neuroscience, Pharmacology. Experience in molecular techniques and an interest in disease model research in animals is essential.

This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References

Akbarian, S. (2014). "Epigenetic mechanisms in schizophrenia." Dialogues in Clinical Neuroscience 16(3): 405-417.

Estes, M. L. and A. K. McAllister (2016). "Maternal immune activation: Implications for neuropsychiatric disorders." Science 353(6301): 772-777.

Knuessel, I. et al. (2014). “Maternal immune activation and abnormal brain development across CNS disorders.” Nature Reviews Neurology 10:643-646.

Ursini, G., G. Punzi, et al. (2017). "Placental gene expression mediates the interaction between obstetrical history and genetic risk for schizophrenia." bioRxiv.

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