AMP and ADP Heterogeneity in Cellular Microdomains
The intracellular environment of cardiomyocytes is remarkably complex, characterized by densely packed membrane structures, organelles, and protein assemblies. This architectural complexity creates distinct microdomains within the cell that may exhibit significant heterogeneity in the distribution of critical metabolic nucleotides, particularly AMP and ADP. Such spatial heterogeneity is not merely a structural curiosity but potentially a crucial determinant of localized metabolic regulation through sensors like AMP-activated protein kinase (AMPK), a major regulator of cellular energy homeostasis.
The primary objective of this research is to develop and apply cutting-edge methodologies to detect and quantify the spatial heterogeneity of AMP and ADP within cardiomyocyte microdomains. To achieve this goal, we will employ AMPfret, a novel fluorescent biosensor specifically designed to monitor adenine nucleotide ratios in living cells.
We aim to:
1. Optimize the signal-to-noise ratio of the AMPfret sensor by integrating advanced biophysical techniques, such as Förster resonance energy transfer (FRET) with scanning fluorescence cross-correlation spectroscopy.
2. Measure local ATP/AMP and ATP/ADP ratios under various physiological and pathophysiological conditions to map the metabolic landscape within cardiomyocytes.
3. Develop mathematical models to analyze the experimental data and predict how microdomain formation influences AMPK signaling cascades and mitochondrial respiratory regulation.
This project offers PhD candidates the opportunity to work at the exciting intersection of multiple disciplines, including cellular and molecular biology, advanced microscopy, biophysics, and systems biology. Depending on their interests and background, candidates can focus on optimizing experimental approaches and measurements or developing mathematical models for data analysis and prediction.
The successful candidate will gain expertise in designing and conducting complex cellular experiments, mastering state-of-the-art imaging techniques, applying molecular biology methodologies, and developing quantitative analytical frameworks. This comprehensive skill set will prepare them for a successful career in biomedical research, where interdisciplinary approaches are increasingly essential for addressing complex biological questions.
By uncovering the spatial dynamics of metabolic regulation in cardiomyocytes, this research has significant implications for understanding cardiac physiology and potentially identifying novel therapeutic targets for heart disease, one of the leading causes of mortality worldwide.
Marko Vendelin (ORCID ID: 0000-0002-6459-0391) is a group leader and the head of the Laboratory of Systems Biology at TalTech. He obtained his PhD in biophysics at TalTech and was a post-doctoral fellow at Joseph Fourier University (Grenoble) and, later, Paris-Sud University (Paris). Marko established the laboratory at TalTech with support from the Wellcome Trust (UK) and has since focused his research on intracellular cardiac physiology with the main interest in the interaction between different processes in cardiac muscle cells. Marko studies intracellular energy fluxes, movement of molecules inside complex environments such as cardiomyocytes, and how local intracellular diffusion gradients impact cell function. For this research, he uses a combination of experimental and mathematical modeling approaches. He has co-authored more than 50 original research articles and several reviews and book chapters. Under his supervision, 6 PhD students have obtained their degrees with majors in physics or gene technology, reflecting the interdisciplinary nature of the laboratory and its methodologies. As a professor of biophysics, Marko teaches courses on Biophysics, Systems Biology, Microscopy, and Mathematical Modeling at TalTech.
Current research focus: cardiac bioenergetics, intracellular energy transfer, intracellular diffusion, biomechanics
Number of Publications: 72
Key Funding: Estonian Research Council
Awards, memberships: Biosciences and Environment – National Science Award (2008); TalTech Young investigator of the year (2007); Member of Biophysical Society
Uwe Schlattner (ORCID ID: 0000-0003-1159-5911) is group leader and laboratory head at the University Grenoble Alpes (UGA) and senior member of the Institut Universitaire de France (IUF). He obtained his PhD at the University of Geneva and spent 10 years at ETH Zürich, Switzerland, as postdoc and habilitated group leader. His research addresses cell energetics, mitochondria and metabolism, in particular kinases in energy homeostasis (nucleoside diphosphate kinases, creatine kinases, AMP-activated protein kinases). Uwe develops innovative tools such as fluorescent sensors and metabolomics protocols to analyse spatiotemporal dynamics of cell metabolism, with recent applications to drug screening. He has co-authored more than 120 research papers and over 50 reviews and book chapters. In 2018 and 2023, he was elected for 5-year terms at IUF. He serves for editorial boards of several journals, including Annual Reviews of Biophysics. At UGA, he teaches courses of Biochemistry, Bioenergetics and Cell Signalling. Uwe has supervised or co-supervised 16 PhD students and 12 postdocs at ETH Zürich and UGA Grenoble. He has been involved in more than a dozen of national (ANR, FRM) and international (EU) research projects with collaborators from both academia (e.g. currently with universities of Bristol, Philadelphia, Toronto, ETH Zürich, TalTech) and industry (e.g. Beiersdorf, SysMed).
Rikke Birkedal (ORCID ID: 0000-0001-6777-7031) is a PI in the Laboratory of Systems Biology at Taltech in Estonia. She obtained her Ph.D. at Aarhus University in Denmark and did her post docs at Université de Paris-Sud, France, and the University of Manchester, UK. Her main research interest is the interplay between morphology, metabolism, excitation-contraction coupling, and mechanical performance in cardiomyocytes from different species. She has co-authored 31 papers and supervised or co-supervised 3 Ph.D. students. She teaches a course in “Muscle and cardiac physiology”.
Applicants should fulfill the following requirements:
• a master’s degree in relevant field
• a clear interest in the topic of the position
• excellent spoken and written English (minimum C1 level)
• strong writing skills (English) that are compatible with doctoral-level requirements
• capacity to work both as an independent researcher and as part of an international team
• capacity and willingness to provide assistance in organizational tasks relevant to the project
For experimental work:
• Experience with laboratory work
• Experience with cell culture
For modeling work:
• programming in Python or C++
• Experience with development of mathematical models
• Experience with solving numerically ODEs and/or PDEs
The following experience is beneficial:
• Experience with microscopy and imaging
• Experience with heart or skeletal muscle physiology
• Working knowledge of SQL
• Working knowledge of statistics and statistical software