Despite extensive research, the molecular mechanisms underpinning these diseases remain poorly understood, and no treatment-modifying therapies currently exist for COPD beyond smoking cessation. Greater understanding of the genetic and cellular mechanisms driving disease has potential to identify new drug targets for treatment.

Recent genome-wide association studies (GWAS) have marked a substantial advance in our understanding. A landmark multi-ancestry GWAS of lung function impairment, comprising over 580,000 participants, identified 559 high-priority candidate causal genes for lung function/COPD through systematic variant-to-gene mapping. These genes implicate biological processes including inflammation, epithelial homeostasis, lung remodelling, and development. However, translating these genetic signals into mechanistic insight has proven slow: evaluating hundreds of candidate genes individually in mammalian systems is expensive, time-consuming, and is ethically questionable.

This PhD project addresses this bottleneck directly. You will use Drosophila melanogaster as a rapid and cost-effective in vivo system to functionally screen GWAS-prioritised candidate genes and identify those with causal roles in airway epithelial biology. Fruit flies share conserved orthologues for the majority of human disease genes, possess a respiratory system (the trachea) with structural and physiological parallels to the human airway, and are amenable to high-throughput genetic manipulation at a scale simply not achievable in mammals.

Working within the research groups of Dr Marios Georgiou (School of Life Sciences) and Professor Ian Sayers (School of Medicine), and in close collaboration with Dr Sofia Araújo (Universitat de Barcelona), you will carry out a systematic RNA interference (RNAi) screen of Drosophila orthologues of the 559 GWAS-prioritised genes. Using Drosophila genetic techniques, you will generate labelled clonal populations in the dorsal thorax epithelium and use high-resolution confocal microscopy to detect effects on cell morphology, cell-cell junctions, and tissue integrity. Genes producing phenotypes in this primary screen will advance to a secondary screen in the Drosophila tracheal system, where effects on airway branching structure and tracheal function will be assessed through imaging and behavioural assays.

Critically, this project does not stop at the fly. Hits from the Drosophila screens will be translated into human systems in the Sayers lab using primary human bronchial epithelial cells, air-liquid interface culture models, and lung tissue from COPD patients and controls.

This studentship is funded by the La Marató de TV3 Foundation as part of a coordinated international project. You will work alongside a second PhD student based in Barcelona, with the opportunity to visit those laboratories as the project progresses. You will gain exceptional multidisciplinary training spanning Drosophila genetics, respiratory cell biology, confocal microscopy, and translational medicine, contributing to research with genuine potential to identify new therapeutic targets for millions of patients worldwide.

We are looking for an enthusiastic and motivated graduate with, or expecting, a 2:1 or first-class honours degree in Genetics, Cell Biology, Biomedical Science, or a related discipline. A Masters degree is desirable but not essential. Prior experience in Drosophila genetics, molecular biology, or microscopy is an advantage but not a requirement; full training will be provided.

The project will last for 3 years.

Despite extensive research, the molecular mechanisms underpinning these diseases remain poorly understood, and no treatment-modifying therapies currently exist for COPD beyond smoking cessation. Greater understanding of the genetic and cellular mechanisms driving disease has potential to identify new drug targets for treatment.

Recent genome-wide association studies (GWAS) have marked a substantial advance in our understanding. A landmark multi-ancestry GWAS of lung function impairment, comprising over 580,000 participants, identified 559 high-priority candidate causal genes for lung function/COPD through systematic variant-to-gene mapping. These genes implicate biological processes including inflammation, epithelial homeostasis, lung remodelling, and development. However, translating these genetic signals into mechanistic insight has proven slow: evaluating hundreds of candidate genes individually in mammalian systems is expensive, time-consuming, and is ethically questionable.

This PhD project addresses this bottleneck directly. You will use Drosophila melanogaster as a rapid and cost-effective in vivo system to functionally screen GWAS-prioritised candidate genes and identify those with causal roles in airway epithelial biology. Fruit flies share conserved orthologues for the majority of human disease genes, possess a respiratory system (the trachea) with structural and physiological parallels to the human airway, and are amenable to high-throughput genetic manipulation at a scale simply not achievable in mammals.

Working within the research groups of Dr Marios Georgiou (School of Life Sciences) and Professor Ian Sayers (School of Medicine), and in close collaboration with Dr Sofia Araújo (Universitat de Barcelona), you will carry out a systematic RNA interference (RNAi) screen of Drosophila orthologues of the 559 GWAS-prioritised genes. Using Drosophila genetic techniques, you will generate labelled clonal populations in the dorsal thorax epithelium and use high-resolution confocal microscopy to detect effects on cell morphology, cell-cell junctions, and tissue integrity. Genes producing phenotypes in this primary screen will advance to a secondary screen in the Drosophila tracheal system, where effects on airway branching structure and tracheal function will be assessed through imaging and behavioural assays.

Critically, this project does not stop at the fly. Hits from the Drosophila screens will be translated into human systems in the Sayers lab using primary human bronchial epithelial cells, air-liquid interface culture models, and lung tissue from COPD patients and controls.

This studentship is funded by the La Marató de TV3 Foundation as part of a coordinated international project. You will work alongside a second PhD student based in Barcelona, with the opportunity to visit those laboratories as the project progresses. You will gain exceptional multidisciplinary training spanning Drosophila genetics, respiratory cell biology, confocal microscopy, and translational medicine, contributing to research with genuine potential to identify new therapeutic targets for millions of patients worldwide.

We are looking for an enthusiastic and motivated graduate with, or expecting, a 2:1 or first-class honours degree in Genetics, Cell Biology, Biomedical Science, or a related discipline. A Masters degree is desirable but not essential. Prior experience in Drosophila genetics, molecular biology, or microscopy is an advantage but not a requirement; full training will be provided.

The project will last for 3 years.