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The research programme Pathomechanisms concentrates on the analysis of disease mechanisms with focus on cardio-vascular diseases (CVDs), in particular heart failure due to myocardial infarction (heart attack), pathological cardiac hypertrophy (heart growth) or cardiotoxic cancer therapies. The overall goal of the programme is to identify molecular changes that are causative for the development of these diseases and are suitable as targets – and possibly as biomarkers.

Within the multiple pathomechanisms that can underly for example heart failure, the scientists address the ones that

  • are of translational potential like cardio-safe targeting of certain kinase (specific enzymes) cascades,

  • represent common pathomechanisms or events in the heart and in cancer, for example cellular growth mechanisms and coagulation (clotting of blood),

  • involve toxic side effects of drugs like cardiotoxicity of cancer drugs and,

  • those that are relevant for the further optimisation of analytical methodologies.

© ISAS / Hannes Woidich

Until today, the molecular causes and the course of many diseases of the cardiovascular system are still largely not understood. Many CVDs have multi-factorial causes – genetic constellations play a part in addition to environmental as well as nutritional factors, platelet disorders or cardiotoxic cancer therapies. To obtain a multidimensional of the pathomechanisms underlying cardiovascular diseases, to enable doctors to diagnose these illnesses earlier in future, and to carry out individual therapies more effectively and with fewer side effects, researchers at ISAS apply methods that comprise genomic, proteomic and metabolomic parameters. They develop, combine, or optimise various analytical technologies to identify disease mechanisms and potential target molecules for the treatment of different cardiovascular diseases.

Development of analytical tools and combination of new methods

The scientists involved in this research programme combine traditional molecular genetic and biochemical methods with high throughput mass spectrometry methods and spectroscopic approaches. This enables them to cover the entire bandwidth of the analysis – from detailed investigation of individual components through to analysis of entire cellular systems.

They aim, for example, to work out spectroscopic and metabolic characteristics of certain diseases with protein or lipid deposition like amyloidosis or Fabry disease in close collaboration with clinician scientist at the Julius-Maximilians-Universität of Würzburg and University of Duisburg-Essen (University Hospital Essen). The scientists at ISAS continue to press ahead intensively with the applications of biospectroscopic analyses, in particular Coherent Anti-Stokes Raman Scattering (CARS) and Raman spectroscopy combined with vibrational microscopy and MALDI (Matrix Assisted Laser Desorption/Ionization) imaging. Moreover, they develop AI methods to optimise the analyses of the obtained data in order to identify early metabolic or structural changes within the myocardium (cardiac muscle).

Gained insights into metabolic events are supplemented by research that aims to optimise nuclear magnetic resonance (NMR) for a longitudinal monitoring of metabolic fluxes with high sensitivity and spatial as well as temporal resolution. It is an analytical method that is of great relevance for a better understanding of cytotoxicity (quality of being toxic to cells) mechanisms of certain drugs.

Application of different model systems

The researchers use cell- and mouse-based model systems that are able to recapitulate central features of CVDs. For example: They work with platelets that can agglomerate and thereby simulate thrombi or cardiomyocytes that beat and thereby serve for the readout of contraction and relaxation. The scientists also work with genetic mouse models that represent a phenotype of pathological heart growth in children or due to lipid depositions in the heart.

Precision medicine: potential of insights into platelet activation

In heart attacks, which are among the top two causes of death worldwide, platelet aggregation plays a central role. ISAS has many years of analytical expertise regarding research into thrombocytes (blood platelets). This includes the comprehensive investigations into the population based proteome of thrombocytes and in-depth research of thrombocyte malfunctions. More insights into platelet activation/inhibition have the potential to further precision medicine for CVDs. Therefore, the researchers at ISAS have been creating a standard platelet data base. It allows the application of machine learning models to predict platelet aggregation and ultimately haemostasis (blood clotting) in patients with heart failure or stroke – a strategy that is being further advanced as a blueprint for other blood cells.