Project 1
From sequence to fitness: A multiscale experimental approach to understanding cardiotonic steroid resistance
Supervisor:
Dr. Shabnam Mohammadi (main supervisor)
Evolutionary and Integrative Physiology Group, Max Planck Institute for Chemical Ecology, Jena
Background:
A central challenge in evolutionary biology is to understand how changes at the molecular level translate into organismal traits and fitness. This project focuses on the Na,K-ATPase, an essential ion pump in animals that has repeatedly evolved resistance to cardiotonic steroids, a class of toxic compounds produced by plants and animals for defense. In muroid rodents, specific amino acid substitutions in the Na,K-ATPase are associated with reduced toxin sensitivity, but the broader physiological consequences of these substitutions remain poorly understood. This system offers a powerful opportunity to investigate how adaptive protein changes are maintained within complex cellular and organismal systems.
Project description:
The PhD candidate will be part of a project that investigates how evolutionary changes in the Na,K-ATPase affect physiology, development, toxin tolerance, and molecular phenotypes in an engineered mouse-line framework. The PhD project may emphasize whole-animal phenotyping, downstream analyses of tissues and blood samples, and/or the integration of organismal, physiological, endocrine, metabolic, histological, and expression-related data. Using mouse lines carrying ancestral reversions of selected resistance-associated substitutions, the project will link defined molecular changes to phenotypes across biological scales. The work will be carried out in close collaboration with researchers specializing in molecular evolution, protein function, cell biology, and in vivo physiology.
The exact balance between in vivo mouse work and sample-based laboratory analyses will be defined according to the candidate’s background, training requirements, project progress, and the expertise available within the collaborative team.
Objectives/Methodology
1. Characterize engineered mouse lines carrying ancestral reversions of selected Na,K-ATPase substitutions using available physiological, biochemical, and molecular data.
2. Assess developmental and fitness-related traits, including growth, survival, and genotype viability from phenotyping data.
3. Evaluate cardiotonic steroid tolerance using ouabain-treatment data.
4. Quantify physiological responses from experimental measurements and biological samples, including blood pressure, cardiac activity, respiration, endocrine responses, and blood chemistry.
5. Assess locomotor and neurological phenotypes from automated behavioral-monitoring data.
6. Analyze tissue samples from relevant organs for expression, histological, and related biochemical analyses.
7. Contribute to randomized, blinded, and sex-balanced experimental designs that account for genotype, cage, litter, batch, and treatment effects.
8. Analyze data with appropriate statistical models and integrate organismal phenotypes with protein- and cell-level results from the wider project.
9. Contribute to publications, conference presentations, and collaborative project meetings.
Candidate profile:
Master’s degree or equivalent in biology, evolutionary biology, physiology, molecular biology, genetics, biochemistry, animal science, or a related field.
● Strong interest in evolutionary biology, genotype-to-phenotype relationships, physiological adaptation, and organismal consequences of molecular evolution.
● Experience with mouse work, animal handling, animal experimentation, behavioral assays, physiology, or analysis of in vivo datasets is highly desirable.
● Familiarity with molecular biology and sample-based techniques such as genotyping, qPCR, tissue processing, ELISA, western blotting, histology, biochemical assays, or related laboratory methods is an advantage.
● Interest in quantitative data analysis and willingness to work with statistical approaches in R or comparable software.
● Ability to work carefully, independently, and responsibly with complex experimental designs, biological samples, collaborative workflows, and animal-welfare requirements.
● Strong organizational skills and ability to coordinate work involving multiple genotypes, treatments, time points, biological sample types, datasets, and collaborators.
● Good communication skills in English and enthusiasm for working in an interdisciplinary team.
Reading:
1. Mohammadi S, Yang L, Bulbert M, Rowland HM. 2022. Defence mitigation by predators of chemically defended prey integrated over the predation sequence and across biological levels with a focus on cardiotonic steroids. Royal Society Open Science. 9:220363.
2. Schoner W, Scheiner-Bobis G. 2007. Endogenous and exogenous cardiac glycosides and their mechanisms of action. American journal of cardiovascular drugs. 7:173-189.
3. Dostanic-Larson I, Lorenz JN, Van Huysse JW, Neumann JC, Moseley AE, Lingrel JB. 2006. Physiological role of the α1-and α2-isoforms of the Na+-K+-ATPase and biological significance of their cardiac glycoside binding site. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2903:R524-R528.