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Projekt Druckansicht

Professur für Umweltinduzierte kardiovaskuläre Degeneration

Fachliche Zuordnung Herz- und Gefäßchirurgie
Gerontobiologie und Geriatrie
Kardiologie, Angiologie
Förderung Förderung von 2012 bis 2019
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 232506016
 
Erstellungsjahr 2020

Zusammenfassung der Projektergebnisse

During the Heisenberg professorship the ongoing projects were pursued further and new avenues of research were started resulting in my continued participation in two successfully renewed collaborative research initiatives and the acquisition of new third party funding. We had previously demonstrated that the catalytic subunit of Telomerase, Telomerase Reverse Transcriptase (TERT) is present not only in the nucleus, but also in mitochondria even of somatic cells. Using newly established unique mouse models we demonstrated for the first time that mitochondrial TERT has protective functions in the cardiovascular system in vivo. In a myocardial infarction (MI) model we showed that it improves mitochondrial respiration and, as a consequence, the functionality of several cell types in the heart resulting in reduced infarct size. We have started to assess the effects of the Telomerase activator TA-65® and revealed not only an activation of mitochondrial TERT, but also improved endothelial cell functionality. These studies are complemented by a human trial in MI patients by one of our clinical collaborators. On the mechanistic side, we have setup experimental systems with our partners at the Moscow Institute of Physics and Technology, which now allow us to study the intracellular movements of TERT in high resolution in living cells. For CDKN1B/p27, known as a nuclear cell cycle inhibitor, we also showed mitochondrial localization, which was enhanced by physiological concentrations of caffeine. Upon translocation into these organelles, p27 improved mitochondrial functions, which was manifested in a reduced infarct size in pre-diabetic animals after caffeine consumption. Analogous to TERT, we have developed a new mouse model containing p27 exclusively in the mitochondria of all cells and organs to assess its mitochondrial functions in vivo. Moreover, together with our Russian partners we are currently generating a recombinant cell-permeable p27 protein targeted to mitochondria to be used in a translational approach in experimental MI. Our years-long investigations of Thioredoxin-1 (Trx-1) have revealed that it is not only an oxidoreductase, but has multiple functions, including protection of the endothelium from apoptosis, which are brought about by interactions with a large number of different proteins that will be further explored in the future. In addition, we are studying the regulation of Trx-1 by environmental factors relevant for cardiovascular diseases. Moreover, we have shown that a small peptide from the protein APEX1 protects Trx-1 from degradation, thereby supporting its anti-apoptotic effect. We are now exploring the applicability of this peptide and potential side effects in lipopolysaccharide-induced endothelial apoptosis as an ex vivo model of sepsis with the long-term goal to develop supportive therapies for this life-threatening condition. We had earlier shown that the transcription factor Grainyhead-like 3 (GRHL3) is critical for proper endothelial functionality, which is compromised in essentially all cardiovascular diseases. We have now shown that some of GRHL3's effects are due to extranuclear interactions with other central mediators of endothelial function. Moreover, we also found a positive impact of Trx-1 on GRHL3. An in depth investigation of these phenomena in the future will provide new insights into molecular mechanisms underlying the maintenance of a functional endothelium and how they are dysregulated in disease. Aging is an independent risk factor for the development of cardiovascular diseases and one hallmark of the aging process is the occurrence of cellular senescence. We have analyzed how carbon nanoparticles, constituents of air pollution, affect the endothelium and the lung ex vivo and in vivo. As aging is accompanied by a decline in mitochondrial functionality, we will investigate how treatment with agents improving mitochondrial functions, e.g. caffeine could delay senescence and thus, dysfunction of the vasculature and the lung. Despite my efforts to make this Heisenberg professorship a success for myself, the IUF and the university, and even though the Medical Faculty and the university had taken all measures for my timely promotion to tenure, the IUF decided for unforeseeable reasons to discontinue cardiovascular research, although I and my group had made a strong contribution to the successful evaluation of the institute. As a consequence, my tenure was delayed for 8 months and deviating from the originally planned joint appointment according to the Jülicher Modell the Medical Faculty took over my position into its budget and will provide me with laboratory space on campus within the next years.

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