Biophotonics and Biosimulation
We combine innovative experimental techniques, new methods of data analysis and mechanism-based modeling to unravel complex relationships between structure, dynamics, and function of cellular and vascular networks in both health and disease.
There are large differences in the design of the vascular networks among different tissues and organs. This difference relates to their specific functions. In the brain, there is no need for large variations in overall flow, but for redirecting flow to local areas where metabolic activity is high. In the kidney, the critical aspect of the circulation is not only to supply the tissues with oxygen and nutrients, but rather to support plasma filtration in each nephron. Many diseases, e.g. hypertension and diabetes, affect the vascular system and change its dynamical responses. We develop high-resolution laser speckle flowmetry and advanced data analysis to assess microvascular structure and vasodynamics in the kidney, retina, and brain.
The increasing demand in the quantitative assessment of interrelations in complex biological systems and development of computational technologies fuel biosimulation as a platform for personalized treatments and drug development. Mathematical models allow us to test whether assumed hypotheses are consistent with observed behavior, to examine the sensitivity of a system to parameter variation, to learn about processes not directly amenable to experimentation, and to predict system’s behavior under conditions not previously experienced. We develop mechanism-based models and employ the concept of synchronization to assess dynamics of biological networks.
Mitochondrial dysfunction is involved in a range of pathological conditions, including cardiovascular diseases, neurodegeneration, diabetes and cancer. At present, most of the studies of isolated mitochondria and mitochondria in cells are performed by fluorescent microscopy, absorption spectroscopy, and measurements of oxygen consumption. The main challenge is that there are no technique for direct, label-free, non-invasive monitoring of the state of mitochondria in living organs. We develop a non-invasive approach based on Raman spectroscopy to assess redox state of the electron transport chain of mitochndria in living cells, tissues, and organs.
Renal microcirculation as an adaptive network
We will provide a full-scale description of the processes in a nephro-vascular structure that can account for the complex interplay between various regulatory mechanisms and to define causes of pathological changes related to hypertension and diabetes. Renal autoregulation is a distributed process enabled by cooperative behavior of multiple nephrons via vascular conducted responses. Degradation of one of network components leads to reduced efficiency of autoregulation. We will map topological and dynamical features of renal autoregulation within the framework of translational studies.
We pioneered the concept of synchronization in renal physiology as means of communication. We developed an experimental approach for renal blood flow imaging using laser speckle imaging techniques. Our experimental studies revealed that neighboring nephrons adjust their tubuloglomerular feedback and myogenic responses by exchange of electrical signals; synchronous clusters differ in the number of nephrons and in the persistence of the cluster in time. Synchronous patterns are disrupted by pathological conditions although the mechanisms remain unknown. We collected statistical data on branching patterns for afferent arterioles using optical clearance and computure tomography methods.
The project is supported by Novo Nordisk Foundation grant for biomedical research.
Modern experimental technologies cannot access dynamics in the deeper regions of the kidney, which makes modeling and biosimulation the only tools available. The large model size and nonlinearities call for creative computer science approaches. We will incorporate statistical topological data, anatomical features of deeper nephrons, and dynamics of autoregulatory mechanisms into a full-kidney-size 3D nephro-vascular model. The model will simulate how disruption of network architecture and dynamics affect the efficiency of renal autoregulation. We will use high-performance computing on graphical processing units (NVIDIA CUDA).
We performed computational study on synchronization of multiple nephrons with symmetrical branching vascular structure and showed that cluster patterns were not always consistent with experimental observations. Our recent model suggested a new implementation of electrical signal propagation along a vascular wall and simulated how renal specific vascular structure can affect renal blood flow patterns and nephron-to-nephron communication.
The project is supported by Data+ Pool, UCPH Strategy 2023 – Talent and Cooperation.
Optical fingerprint of mitochondria
At present, widely-used methods for the quantification of electron transport chain activity in mitochondria are biochemical techniques employing measuring of their respiration rate and the amount of certain complexes. We propose to illuminate the molecules of the mitochondrial electron-transport chain with laser light to detect, record, and interpret their optical fingerprints – a unique set of bond-vibrational energies providing information about redox state and conformation of electron-transport chain components. By choosing the excitation wavelength it is possible to obtain Raman scattering predominantly from different cytochromes.
We studied redox state of reduced cytochromes c, c1 and b of complexes II and III in mitochondria of live cardiomyocytes, skeletal myocytes, macrophages, stem cells, cancer cell lines, in a perfused rat heart (under normal and ischemic conditions), and brain slices (under aging conditions). We developed in vivo experimental approach based on surface-enhanced Raman spectroscopy to perform localization and study of hemoglobin properties and signaling pathways in living erythrocyte.
The project is supported through collaboration grants with Moscow State University, Russia.
2020 PI, UCPH Data+ pool UCPH Strategy 2023, Virtual kidney
2020 PI, UCPH Strategy 2023 grant research-integrating teaching activities, Physiological modeling computer cluster PIONEER
2019–2022 PI, Novo Nordisk Foundation, Renal autoregulation in health and disease
2017–2016 Named participant, Danish Agency for Science, Technology and Innovation, Bilateral network on nanocluster-based functional materials
2013–2016 Named participant, UCPH’s Funds, Dynamical systems — Mathematical modeling and statistical methodology for the social, health and natural sciences
2009–2013 PI, The Danish Council for Independent Research/Natural Sciences, In vivo Raman spectroscopy and mechanism-based modeling of erythrocyte properties
2007–2010 PI, The Danish Council for Independent Research/Natural Sciences, Mechanism-based modeling of cellular interactions: From physics to systems biology
2004-2009 Member of the EU Network of Excellence Biosim – A new tool in drug development