Research projects

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Decoding Temporal Windows for Mitochondrial Intervention Across Species Using Data-Driven Approaches (available as IPhD)

Supervisor: Alberto Sanz

MSc choices: Biomedical Sciences, Bioinformatics, Biotechnology, Immunology & Inflammatory Disease, Medical Genetics & Genomics, Precision Medicine.

Project description: 

Mutations in genes encoding mitochondrial OXPHOS components often cause devastating diseases. Paradoxically, lifespan can be extended in worms, flies, and mice by partially impairing mitochondrial function. Why this occurs remains poorly understood. The Sanz laboratory has revealed that the timing of mitochondrial dysfunction is critical—similar interventions produce opposing outcomes depending on when they are applied. This project aims to systematically identify conserved patterns that explain this temporal dependency.

We will analyse RNAseq and proteomics datasets from Drosophila melanogaster, Caenorhabditis elegans, Mus musculus, and Homo sapiens, comparing short- and long-lived species. We will assess mRNA and protein expression across tissues and developmental stages, quantifying correlations between transcript and protein levels. Using machine learning, we will identify conserved expression profiles that predict lifespan outcomes.

Guided by these insights, we will use state-of-the-art genome editing in Drosophila to modulate mitochondrial function with spatiotemporal precision, targeting specific tissues and developmental windows to generate new long-lived flies.

By uncovering the timing and location rules that govern mitochondrial influence on longevity, this work will establish a foundation for future interventions to extend human healthspan.

Techniques:

• Data mining
• Transcriptomics
• Proteomics
• Statistical Analysis
• Machine Learning
• Genetics
• Molecular Biology

References:

1. Developmental mitochondrial complex I activity determines lifespan. Stefanatos R, Robertson F, Castejon-Vega B, Yu Y, Uribe AH, Myers K, Kataura T, Korolchuk VI, Maddocks ODK, Martins LM, Sanz A. EMBO Rep. 2025 Apr;26(8):1957-1983

2. NLRP1 inflammasome promotes senescence and senescence-associated secretory phenotype. Muela-Zarzuela I, Suarez-Rivero JM, Gallardo-Orihuela A, Wang C, Izawa K, de Gregorio-Procopio M, Couillin I, Ryffel B, Kitaura J, Sanz A, von Zglinicki T, Mbalaviele G, Cordero MD. Inflamm Res. 2024 Aug;73(8):1253-1266.

3. Autophagy promotes cell survival by maintaining NAD levels.
   Kataura T, Sedlackova L, Otten EG, Kumari R, Shapira D, Scialo F, Stefanatos R, Ishikawa KI, Kelly G, Seranova E, Sun C, Maetzel D, Kenneth N, Trushin S, Zhang T, Trushina E, Bascom CC, Tasseff R, Isfort RJ, Oblong JE, Miwa S, Lazarou M, Jaenisch R, Imoto M, Saiki S, Papamichos-Chronakis M, Manjithaya R, Maddocks ODK, Sanz A, Sarkar S, Korolchuk VI.
   Dev Cell. 2022 Nov 21;57(22):2584-2598.e11.

4. Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies. Graham C, Stefanatos R, Yek AEH, Spriggs RV, Loh SHY, Uribe AH, Zhang T, Martins LM, Maddocks ODK, Scialo F, Sanz A. Geroscience. 2022 Aug;44(4):1961-1974.

5. Mitochondrial complex I derived ROS regulate stress adaptation in Drosophila melanogaster. Scialò F, Sriram A, Stefanatos R, Spriggs RV, Loh SHY, Martins LM, Sanz A.Redox Biol. 2020 May;32:101450. 

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Overview

Systems Biology draws on the strengths of molecular and cell biology to try to build an integrative picture of how organisms work. Implicit in the approach is big data (coming from imaging, microarray, RNAseq, proteomics or metabolomics, for which we are very well equipped), together with mathematical and computational biology to draw higher-level insights. Systems biology also works very well with genetic model organisms, such as yeast, Drosophila or Arabidopsis; or in human biomedicine.

Through their research interests in drug development, biotechnology and clinical applications, many of our project supervisors have strong links with pharmaceutical and agrochemical industry. The interdisciplinary nature of systems biology means that these highly active supervisors have international collaborations both with other Universities and industry. Funds are available through the College of Medical, Veterinary & Life Sciences to allow visits to international laboratories where part of your project can be carried out. This provides an excellent opportunity for networking and increasing your scientific knowledge and skill set.

Research topics are allied to ongoing research within the School, the majority of which are basic science projects. A variety of multi-disciplinary research approaches are applied, including biochemistry, molecular biology, molecular genetics, materials science, polyomics (genomics, transcriptomics, proteomics, metabolomics etc), bioinformatics, structural biology, microscopy and imaging techniques. Specific areas of interest include:

• modelling organ specificity in the plant circadian clock
• post-genomic insights into tissue function and control in Drosophila
• optimising recombinant protein expression and secretion in mammalian cells
• systems biology approaches of stress-induced plasticity of the mitochondrial intermembrane space
• light control of local and long distance phytohormone signalling in Arabidopsis
• quantitative systems biology of membrane transport and cellular homeostasis
• systems biology of gas exchange and photosynthesis, from molecule to the field
• materials and metabolomics for identification of stem cell fate modifying metabolites
• analysis and integration of large omics datasets

Study options

PhD

• Duration: 3/4 years full-time; 5 years part-time

Individual research projects are tailored around the expertise of principal investigators.

MSc (Research)

• Duration: 1 year full-time; 2 years part-time