(BHF Acc) Uncovering New Genetic Mechanisms, Biomarkers and Drug Targets for Hypertension – from Systems Biology to Precision Medicine

University of Manchester

Faculty of Biology, Medicine and Health

Project Description

We propose that using a combination of genome-wide genotyping, RNA-sequencing, epigenome analysis, precision phenotyping, and the cutting-edge bioinformatic, statistical and mathematical strategies will uncover molecular footprints of elevated BP and new diagnostic and therapeutic opportunities for hypertension.

Specific aims:

  1. To identify genetic signatures of hypertension
  2. To integrate the identified molecular footprints of hypertension with functional annotations
  3. To characterise the causal relationships between the specific variants, genes and hypertension/its downstream complications
  4. To uncover new bio-markers of hypertension-mediated organ damage and new drug targets for hypertension by exploiting a concept of “druggable” genome

For Aim 1 of the project, the student will combine genotype with expression-, DNA methylation- and alternative splicing, apply colocalisation and transcriptome imputation to generate the list of robust molecular signatures of hypertension in BP-relevant tissues. To enhance biological interpretation of the findings, for Aim 2, the student will then combine the results of analyses conducted for Aim 1 with regulatory annotations from resources of functional genomic elements [i.e. ENCODE DNase I hypersensitive sites (DHSs) and chromatin immunoprecipitation sequencing (ChIP-seq) peaks for core histone marks]. Furthermore, the student will use the single-cell sequencing datasets to map the identified signatures onto the specific cell lineages. The major emphasis for Aim 3 of the project will be to exploit UK Biobank data and apply 2-stage Mendelian randomisation as well as new machine learning methods to characterise the chain of molecular events – from sequence (DNA variant) to consequence (hypertension and its target organ damage). For Aim 4, the student will integrate pharmacological resources with information derived at earlier stages of the project and investigate new therapeutic opportunities for hypertension (i.e. through pairing of specific targets with pharmacological/chemical compounds). This analysis will identify new promising drug repurposing opportunities for hypertension.

Funding Information

This project is to be funded under the BHF Accelerator Award. Studentship funding is for a duration of three years to commence in September 2020 and covers UK/EU tuition fees and a UKRI stipend (£15,009 per annum 2019/20). Due to funding restrictions the studentship is open to UK and EU nationals with 3 years residency in the UK.

Eligibility Requirements

Applications are invited from UK/EU nationals only. Candidates must hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject (biological sciences, bioinformatics, statistics or computational sciences). A related master’s degree would be an advantage.

Application Process

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 BHF Accelerator Award website.

Supplementary Information

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. Xu X, et al. Molecular insights into genome-wide association studies of chronic kidney disease-defining traits. Nat Commun. 2018;9:4800.

Rowland J, et al. Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics. Kidney Int. 2019;95:624-635.

Morris AP, et al. Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies. Nat Commun. 2019;10:29.

Finan C, et al. The druggable genome and support for target identification and validation in drug development. Sci Transl Med. 2017;9(383).

To apply for this PhD, please email maciej.tomaszewski@manchester.ac.uk.

Before sending your email, please double check you have followed all guidelines in this listing and have included a reference number if asked to do so.

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