SysMito
Systems biology based analysis of mitochondrial metabolism as a driver of inflammation in cardiovascular disease development (SysMito) (2024-2026)
Project No. 5,2,1,1.i.0/2/24/I/CFLA/005
Source of funding: financed under the European Union's Recovery and Resilience Facility and the national budget
Project period: 01.04.2024. – 31.03.2026. (24 months)
Total budget: 200 000 EUR
Project coordinator: Egils Stalidzans
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Objective:
SysMito project aims to apply systems biology methods to identify and quantify in form of mathematical models’ inflammation related metabolic processes that can be used identifying rational CVD treatment strategies.
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Summary:
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Atherosclerotic cardiovascular disease (CVD) is a leading cause of mortality and disability globally. In the initial phases of CVD, crucial events such as inflammatory activation, endothelial dysfunction, lipid profile changes, and oxidative stress occur. These disruptions are intricately connected to mitochondrial dysfunction, suggesting it as a pivotal factor in atherosclerosis development and a potential target for novel therapeutic interventions or diagnostics. A substantial amount of longitudinal omics data has been collected on CVD-related inflammation processes, leading to various hypotheses that occasionally contradict each other.
The project aims to apply systems biology approach studying the inflammation process, through constructing mechanistic mathematical models to simulate molecular interactions, transport, and other processes. This approach facilitates the extraction of additional knowledge about molecular interaction mechanisms from available data sources and confirm or reject different hypotheses about mitochondrial role in inflammation. Publicly available multi-omics data will be integrated in genome scale constraint based stoichiometric models and pathway scale kinetic models.
The obtained mechanistic models can be further used for the development of treatments and therapies to control CVD related inflammation processes targeting mitochondrial metabolism or it’s control networks.
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Four constraint-based models have been developed using the MitoCore reconstruction of human central metabolism based on transcriptomics data for macrophages and foam cells – control cell cultures and cell cultures from atherosclerotic patients.
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Using the macrophage control samples’ ATP production rate as a reference, the rates for atherosclerotic macrophages, control foam cells, and atherosclerotic foam cells are 91%, 81%, and 80%, respectively. The rate limiting enzymes for further increase of ATP production are in different complexes of the electron transport chain. In both atherosclerotic cell types, the most dysregulated subsystems are reactive oxygen species (ROS) defense, serine and glycine biosynthesis and GABA shunt. In the case of foam cells, the most dysregulated subsystems are heme degradation, pentose phosphate pathway, glutamine synthesis, and threonine degradation.
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Metabolic reprogramming in central human metabolism has been observed, indicating common features for both foam cell cultures as well as common features for both atherosclerotic cell cultures. The average up-regulations and down-regulations of specific metabolic subsystems are up to 60% compared to macrophage control cells.āāāā
