Project 9
Genetics and genomics of primary aldosteronis
Detection of secondary forms of hypertension is key to targeted management of the underlying disease and prevention of cardiovascular complications. We hypothesize that understanding the mechanisms involved in the development of primary aldosteronism (PA) allows improved diagnosis and treatment of arterial hypertension in the general population. We have performed a genome-wide case-control association studies (GWAS) to identify susceptibility genes for PA. Cell studies have allowed selecting two genes conferring increased risk for PA. Aim of this project is to follow up these genes in vivo in genetically modified mouse models to investigated their role in the development of PA.
The identified genes will be inactivated in the entire animal or selectively in the zona glomerulosa (ZG) of the adrenal cortex. ZG-specific inactivation will be achieved by crossing mice carrying a floxed allele with mice expressing the Cre recombinase under the control of the promoter of the Cyp11b2 gene. The adrenal and vascular phenotypes will be explored at the morphological, functional and molecular level. Hormonal exploration of the adrenal gland function will include steroid profiling and analysis of the renin-angiotensin system using mass spectrometry. Investigations will be performed in both sexes in young and ageing animals. The transcriptome and miRNome of the adrenal cortex of knock-out mice will be studied in comparison with wild-type mice to get mechanistic insight on phenotypic alterations. Bioinformatic analyses will be used to identify targets and pathways modified in the adrenal cortex and genomic changes will be followed up by performing phenotypic and mechanistic studies in differentiated cell lines from the human adrenal cortex. Secondments are planned at the University of Glasgow, the University of Maastricht and at Attoquant.
Requirements:
- Qualifications: Masters Degree (MSc, MS, MRes) in one of the following areas: biomedical science, biotechnology, biochemistry, molecular biology.
- Experience: Experience in experimental laboratory work is essential. Practical experience of animal handling, knowledge and/or experience of the regulations covering animal experimentation, experience of molecular science laboratory procedures are desirable.
- Knowledge & skills:Knowledge on pathophysiological mechanisms of disease, skills in animal manipulations and/or molecular biology are desirable.
- Attitude and disposition: Good interpersonal skills to allow working as part of a team, strong work ethics, self motivation, initiative and independent thought/working, problem solving skills including a flexible and pragmatic approach.
- Other circumstances: Although knowledge of French is not a prerequisite, the applicant will be offered French classes in order to interact with the local PhD programme.
Secondments: In the Davies lab at UGLA, ESR9 will receive training on high-throughput profiling and functional analysis of miRNA (2 months). 2. In the Isaacs lab at UM, ESR9 will receive training on bioinformatics and biostatistical tools applied to the analysis of omics data (0.5 months). 3. ESR9 will be trained on mass spectrometry and analytical method development and validation at Attoquant (1.5 month).