Periodic Reporting for period 1 - TIKKS (Innovative insight into the endogenous kallikrein-kinin system in tissue in health and disease state)
Periodo di rendicontazione: 2022-05-01 al 2024-04-30
This project was early terminated at month 8 of the outgoing phase at the BAylor College of Medicine as the researcher was offered a professorship at a German university.
Cardiovascular diseases, cancer, and sepsis are the leading causes of death worldwide. In all of them, a strong involvement of the endogenous kallikrein-kinin system (KKS) is postulated. However, the KKS is only rudimentarily understood and intensive research needed, which is also reflected by the large proportion of developed compounds showing insufficient efficacy in clinical trial phase. The KKS is a 2-arm cascade that is present in both the blood as well as the tissue and its actions are mediated by the so-called kinins. Comprehensive insight into the cascade is greatly hindered by the lack of appropriate bioanalytical techniques. While the fellow has recently developed an innovative mass spectrometric method for the plasma KKS and applied in clinical studies, the tissue KKS has not yet been investigated, although the physiological action is likely exerted only in tissue. The advances in mass spectrometric imaging are currently used for metabolomics or mapping of biomolecules in tissue, but appear to be highly promising also for kinin detection and subsequently to study the role of tissue kinins in (patho-)physiology. The fellow with his key expertise in targeted mass spectrometric kinin quantification will use different mass spectrometric imaging techniques (DESI, MALDI, MasSpec Pen) to evaluate the tissue KKS. Hence, the TIKKS project is to first time study the presence, distribution, metabolism and overall profile of kinins in different (diseased) tissues by mass spectrometric imaging. For this purpose, various malignant tissues are examined as a main objective and subsequently extended to cardiovascular diseases and angioedema. This innovative approach will allow the fellow to uniquely investigate physiology and pathophysiology across both arms of the KKS (tissue & plasma) and therefore strengthen him on his path to his own professorship. The combined power of the innovative imaging approach and the already established mass spectrometric platform for plasma KKS will critically accelerate the discovery of promising drug targets for non-communicable diseases.
Cardiovascular diseases, cancer, and sepsis are the leading causes of death worldwide. In all of them, a strong involvement of the endogenous kallikrein-kinin system (KKS) is postulated. However, the KKS is only rudimentarily understood and intensive research needed, which is also reflected by the large proportion of developed compounds showing insufficient efficacy in clinical trial phase. The KKS is a 2-arm cascade that is present in both the blood as well as the tissue and its actions are mediated by the so-called kinins. Comprehensive insight into the cascade is greatly hindered by the lack of appropriate bioanalytical techniques. While the fellow has recently developed an innovative mass spectrometric method for the plasma KKS and applied in clinical studies, the tissue KKS has not yet been investigated, although the physiological action is likely exerted only in tissue. The advances in mass spectrometric imaging are currently used for metabolomics or mapping of biomolecules in tissue, but appear to be highly promising also for kinin detection and subsequently to study the role of tissue kinins in (patho-)physiology. The fellow with his key expertise in targeted mass spectrometric kinin quantification will use different mass spectrometric imaging techniques (DESI, MALDI, MasSpec Pen) to evaluate the tissue KKS. Hence, the TIKKS project is to first time study the presence, distribution, metabolism and overall profile of kinins in different (diseased) tissues by mass spectrometric imaging. For this purpose, various malignant tissues are examined as a main objective and subsequently extended to cardiovascular diseases and angioedema. This innovative approach will allow the fellow to uniquely investigate physiology and pathophysiology across both arms of the KKS (tissue & plasma) and therefore strengthen him on his path to his own professorship. The combined power of the innovative imaging approach and the already established mass spectrometric platform for plasma KKS will critically accelerate the discovery of promising drug targets for non-communicable diseases.
As the applicant was offered a professorship at a German university, the project was terminated early. Up to this point, he had been working on experiments aiming to optimize his experimental mass spectrometer imaging setup. The focus here was on improving the intensity in order to be able to detect low abundant kinins in the tissue. Commercially available instruments on which the applicant was allowed to work were not sensitive enough for direct kinin detection on tissue. The latter explains the need for optimization of his experimental setting. Endogenous tissue samples were not measured until the end of the project.