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(MRC DTP) Developmental programming of heart disease by prenatal hypoxia: in vivo disease susceptibility and underlying epigenetic mechanisms

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  • Full or part time
    Dr G Galli
    Prof A Trafford
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

A lack of oxygen to the developing fetus (prenatal hypoxia) is a common occurrence in complicated pregnancies. Adult offspring from hypoxic pregnancies have cardiac abnormalities, such as impaired diastolic function, enhanced responsiveness to sympathetic stimulation and increased susceptibility to in vitro ischemia/reperfusion injury1. While this phenotype is often cited in the literature as being a precursor to disease2, no study has directly tested whether offspring are more susceptible to cardiovascular risk factors, such as hypertension. Establishing these relationships are important, because understanding comorbidities will help to predict, prevent and treat instances of heart disease. Therefore, the first objective of this project is to test the hypothesis that adult offspring from hypoxic pregnancies are more susceptible to developing heart failure induced by chronic hypertension. To address this hypothesis, we will study the effects of prenatal hypoxia on the hearts of adult rats chronically exposed to hypertensive stimuli. In vivo heart function will be measured with echocardiography, and in vitro structure and cellular function will be investigated with histology and fluorescent microscopy, respectively. Importantly, the study will investigate outcomes in both males and females, which addresses the urgent need for more gender-balanced cardiovascular research to improve cardiac health in women.

In addition to studying cardiac susceptibility to disease, the project also seeks to define the mechanistic basis for cardiac dysfunction in offspring from hypoxic pregnancies. The Galli and Trafford labs are currently investigating the hypothesis that prenatal hypoxia programmes maladaptive cardiomyocyte Ca2+ handling which leads to the development of cardiac dysfunction. However, the molecular basis of the cardiac phenotype is entirely unknown. While numerous possibilities exist, several studies have shown environmental stress during development can trigger epigenetic modifications, such as DNA methylation. Identifying these mechanisms has clear translational relevance, as genomic and pharmacological techniques to manipulate epigenetic modifications are currently being developed; these drugs have already entered clinical trials with some success in cancer. Therefore, the second main objective of this project is to test the hypothesis that prenatal hypoxia pathologically alters the methylation pattern of genes associated with cardiac function. This hypothesis will be addressed by measuring whole genome DNA methylation in purified cardiomyocytes through methylated DNA immunoprecipitation followed by sequencing of the genomic fraction enriched for DNA methylation3. In order to understand links between DNA methylation disturbances and gene function, we will also assess gene expression with RNA seq. The sequencing data will be interpreted and integrated through bioinformatics analyses4.

https://www.research.manchester.ac.uk/portal/gina.galli.html
https://www.research.manchester.ac.uk/portal/andrew.w.trafford.html
https://liu.se/en/employee/cargu13

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

(1) Niu et al., 2018. Maternal Allopurinol Prevents Cardiac Dysfunction in Adult Male Offspring Programmed by Chronic Hypoxia During Pregnancy. Hypertension. 2018 Oct; 72(4): 971–978.

(2) Giussani DA & Davidge ST. Developmental programming of cardiovascular disease by prenatal hypoxia.
J Dev Orig Health Dis. 2013 Oct;4(5):328-37.

(3) Guerrero-Bosagna C, Jensen P. Optimized method for methylated DNA immuno-precipitation. MethodsX. 2015 Oct 19;2:432-9.

(4) Guerrero-Bosagna et al. Environmentally induced epigenetic transgenerational inheritance of altered Sertoli cell transcriptome and epigenome: molecular etiology of male infertility. PLoS One. 2013;8(3):e59922



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