2026-27 Project (Southgate & Dobbins)

From interaction to intervention: Multi-omics prioritisation and functional validation of a novel therapeutic avenue in pulmonary hypertension

SUPERVISORY TEAM

Supervisor

Dr Laura Southgate at City St George’s
School of Health & Medical Sciences, Department of Molecular and Biomedical Sciences
Email: lasouthg@citystgeorges.ac.uk

Co-Supervisor

Dr Sara Dobbins at City St George’s
School of Health & Medical Sciences, Department of Molecular and Biomedical Sciences
Email: sdobbins@citystgeorges.ac.uk

PROJECT SUMMARY

Project Summary

Pulmonary arterial hypertension (PAH) is a rare but life-threatening condition affecting the lungs and heart. Our team recently identified a novel protein-protein interaction (PPI) involving ATP13A3, a gene newly implicated in PAH. This PhD project offers an exciting opportunity to investigate the functional and therapeutic relevance of this interaction using an interdisciplinary approach that combines data science, genomics and molecular biology he successful applicant will work with large-scale genomic datasets (e.g. UK Biobank, 100K Genomes Project), apply cutting-edge computational tools (e.g. AlphaFold, RNA-seq analysis) and validate findings in human cell models. The project is highly flexible and designed to build strong quantitative skills while contributing to the discovery of novel disease mechanisms and potential drug targets. If you’re interested in rare disease genomics, precision medicine or translational bioinformatics, this project offers an ideal training environment in a collaborative, supportive lab with access to excellent datasets and expertise.

Project Key Words

Bioinformatics; Genomics; Protein Networks; Vascular Biology

MRC LID Themes

  1. Health Data Science
  2. Translational and Implementation Research

Skills

MRC Core Skills

  1. Quantitative skills
  2. Interdisciplinary skills

Skills we expect a student to develop/acquire whilst pursuing this project:

This project will equip the student with a range of versatile skills including bioinformatics and data science skills (e.g. R, Python) and molecular biology skills (e.g. cell culture, imaging)

Routes

Which route/s are available with this project?

  • 1+4 = Yes
  • +4 = Yes

Possible Master’s programme options identified by supervisory team for 1+4 applicants:

  • City St Georges – MRes/MSc Translational Medicine
  • City St Georges – MSc Applied Biomedical Science
  • City St Georges – MSc Genomic Medicine

Full-time/Part-time Study

Is this project available for full-time study? Yes
Is this project available for part-time study? Yes

Location & Travel

Students funded through MRC LID are expected to work on site at their primary institution. At a minimum, all students must meet the institutional research degree regulations and expectations about onsite working and under this scheme they may be expected to work onsite (in-person) more frequently. Students may also be required to travel for conferences (up to 3 over the duration of the studentship), and for any required training for research degree study and training. Other travel expectations and opportunities highlighted by the supervisory team are noted below.

Day-to-day work (primary location) for the duration of this research degree project will be at: City St George’s – Tooting campus, London

Travel requirements for this project: Applicants should be willing to travel nationally and internationally to attend meetings with collaborators, but will not be expected to work for significant periods outside of London.

Eligibility/Requirements

Particular prior educational requirements for a student undertaking this project

  • Minimum standard institutional eligibility criteria for doctoral study at City St George’s
  • Applicants must have obtained, or be about to obtain, an MSc/MRes or BSc (2:1 or above) in biological sciences, molecular biology, genetics, bioinformatics or a related life sciences field
  • Candidates with prior experience in bioinformatics, computational biology or systems biology are particularly encouraged to apply

Other useful information

  • Potential Industrial CASE (iCASE) conversion? = No

PROJECT IN MORE DETAIL

Scientific description of this research project

Background:
Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease with substantial genetic heterogeneity. While BMPR2 haploinsufficiency represents the major heritable risk factor, the genetic basis of idiopathic PAH remains largely unresolved. Our group identified ATP13A3 as a novel risk gene with semi-dominant, dose-dependent inheritance in adult- and paediatric-onset PAH [Gräf et al. 2018; Machado et al. 2023]. To explore its cellular role, we performed a yeast two-hybrid screen and detected a novel protein-protein interaction (PPI), supporting a role for ATP13A3 in the polyamine metabolic pathway. These findings offer a new avenue for therapeutic intervention and improved vascular health.

Aim:
The project will investigate this novel interactor, using computational and experimental approaches to evaluate its functional and therapeutic relevance in PAH.

Project objectives:

  1. Integrate multi-omics data to define the ATP13A3-interactor network in PAH and explore therapeutic potential: Using transcriptomic, proteomic and regulatory datasets (LungMap, GTEx, Hi-C) the co-expression and signalling networks will be characterised in disease-relevant tissues. Public drug-target databases (DrugBank, ChEMBL) will identify candidate compounds targeting polyamine metabolism.  
  2. Evaluate the genetic contribution of this novel interactor to PAH: Leveraging population-scale (100,000 Genomes Project, UK Biobank, other genome projects) and disease-specific datasets, rare variant burden will be evaluated alongside electronic health records and genome-wide association study (GWAS) data to assess pathogenicity. 
  3. Apply structural modelling and in silico tools to assess the interaction: 3D protein modelling, interface prediction and in silico mutagenesis (AlphaFold, FoldX) will be used to test how PAH-associated variants may disrupt the interaction. 
  4. Functionally validate the interaction and variant effects in human vascular cell models: Co-immunoprecipitation, proximity ligation assays and functional tests will be performed to confirm the interaction and assess the impact of selected disease-associated variants.   

Techniques to be used:  

  1. Multi-omics and genetic data analysis (genome sequencing, RNA-seq, GWAS, Hi-C) 
  2. Computational modelling and bioinformatics (3D protein modelling, R, Python) 
  3. Molecular biology techniques (cloning, mutagenesis, co-immunoprecipitation, proximity ligation assay, cell culture) and imaging (confocal microscopy).   

Confirmed availability of any required databases or specialist materials:
Access to 100KGP and UKBB is available to City St George’s; the supervisors are experienced with these resources. RNAseq datasets of PAH patients (blood and lung) are accessible via existing collaboration (Dr Chris Rhodes, Imperial) and published sources [Asosingh et al. 2021; Tang et al. 2024]. PAH rare variant association (RVAS) and GWAS datasets are similarly available [Graf et al. 2018; Rhodes et al. 2019]. Additional datasets will be sought during the project. Other resources are publicly available (LungMap, GTex, Drugbank, AlphaFold).   

Potential risks to the project and plans for their mitigation:
As this project primarily relies on public datasets, risks are relatively low. The main challenge is functional validation, which may require optimisation to yield robust results. To mitigate this, the project is designed with flexibility – alternative strategies include:

  1. genotype-phenotype correlation analyses with 100KGP and UKBB data;
  2. additional computational methods such as pathway enrichment and network modelling; and
  3. complementary in vitro assays or collaborations with specialist labs for advanced functional studies.   This adaptive approach will ensure steady progress despite experimental uncertainties.

Further reading

Relevant preprints and/or open access articles:
(DOI = Digital Object Identifier)

Other pre-application materials: None

Additional information from the supervisory team

The supervisory team has provided a recording for prospective applicants who are interested in their project. This recording should be watched before any discussions begin with the supervisory team.

Southgate & Dobbins Recording

MRC LID LINKS

To apply for a studentship: MRC LID How to Apply
Full list of available projects: MRC LID Projects
For more information about the DTP: MRC LID About Us

Comments are closed.