Delineating PLATElet-induced sex-specific responses in Calcific Aortic Valve disease using 3D-bioprinting and proteomics.

Projektbeschreibung

Thrombozytenvermittelte Mechanismen bei Aortenklappenerkrankungen

Die Aortenklappenkalzifikation ist durch eine pathologische Verdickung und Verkalkung der Aortenklappe gekennzeichnet. Immer mehr Erkenntnisse deuten darauf hin, dass das Fortschreiten der Aortenklappenkalzifikation geschlechtsspezifische Unterschiede und morphologische Variationen aufweist, wobei die zugrunde liegende Ätiologie jedoch noch immer unzureichend erforscht ist. Das Ziel des innerhalb der Marie-Skłodowska-Curie-Maßnahmen unterstützten Projekts PlateCAV-3D besteht darin, die Rolle aktivierter Thrombozyten bei der frühen Aortenklappenkalzifikation zu untersuchen. Die Hypothese lautet, dass Thrombozytenmediatoren wie TGF-β den Übergang von Endothel- zu Mesenchymzellen auslösen und zur Aortenklappenkalzifikation beitragen. Die Forschenden werden einen interdisziplinären Ansatz verfolgen, um durch Thrombozyten beeinflusste Faktoren der Aortenklappenkalzifikation zu ermitteln und zu validieren. Die Studie wird erwartungsgemäß in neuen Therapieansätzen und alternativen Interventionen zur Herzklappenersatzchirurgie münden.

Ziel

Calcific aortic valve disease (CAVD) is an increasing global health burden. Once symptomatic and untreated, CAVD confers a 2-year mortality rate of ~50%. Crucially, costly and highly specialised valve replacement surgery remains the only treatment. Additionally, while male and female patients present with calcific or fibrotic tissue degeneration, respectively, experimental studies mostly use male models. The rising disease burden, lack of understanding of differential pathophysiological mechanisms underlying CAVD onset and progression, and inequality in accessing surgical intervention impose the need to uncover novel therapeutic targets to delay disease development. Haemostatic alterations, including platelet activation, are implicated in CAVD, and may particularly compromise patients with bicuspid vs. tricuspid valves. Endothelial-to-mesenchymal transition of valvular endothelial cells is a hallmark of CAVD onset and potently induced by platelet-derived mediators such as TGF-β, suggesting the direct involvement of activated platelets. The differential platelet-mediated mechanisms underlying both the valve morphology- and sex-specific disease
pathophysiology remain elusive. We will perform unbiased global proteomics to identify novel platelet-derived mediators in the onset of CAVD. These mediators will be used to induce CAVD in a biologically relevant, sex-specific 3D bioprinted in vitro model. By combining histopathology, imaging, proteomics, and bioinformatics, PlateCAV-3D will characterise the contribution of platelets to the onset of CAVD and infer valve morphology- and sex-specific disease trajectories to uncover novel therapeutic targets. Identification of patient-specific therapeutic target candidates provides the opportunity to design clinical trials to decelerate disease onset/progression and ultimately diminish the need for surgical intervention, globally decreasing health care costs, and eradicating the inequality in access to interventional therapies.