General relativity (GR) is a very elegant theory from the conceptual point of view and a very successful one from the experimental side. However, there are several conceptual reasons, such as the singularity problem, that motivate the study of extensions of GR. The study of black hole physics will play a pivotal role in the understanding of new physics beyond general relativity. In fact, black holes hide in their interior theoretical evidence of the breakdown of GR and they are compact objects where strong gravity effects are nonnegligible. The research proposal "The End STate of GRavitational collapse: black holes or else? (TESTGR)" focuses on the study of several aspects associated with the black hole singularity problem looking for possible evidence of new physics beyond GR, to understand how the modifications would manifest and how to detect them. The proposed research comprises both theoretical and phenomenological studies. It is divided into 3 working packages (WPs) that are strongly interconnected but that can be studied independently. The first WP studies the mechanism leading to the formation of black holes mimickers. The second WP addresses crucial issues related to the viability and stability of the identified classes of spacetimes. Finally, the last WP focuses on the interplay with observations. This research proposal is particularly timing as the LIGO/VIRGO/KAGRA detectors, the EHT, as well as the next generation of earth and space-based interferometers, will collect plenty of data in future years. This leads to a growing necessity for theoretical studies beyond general relativity to understand if the data contains evidence of new physics that can revolutionize our understanding of nature.

Degenerative aortic valve stenosis is the most common acquire heart valve disease and will continue to increase as a result of an aging population. There is currently no medical therapy established to halt progression of aortic stenosis and the only definitive treatment is aortic valve replacement either by surgery or transcatheter aortic valve replacement (TAVR). Without valve replacement, the 2 year mortality rate approximates 50 % once patients are symptomatic. Although a number of general risk factors have been described for developing calcified aortic valve disease, risk prediction for progression of CAVD to severe stenosis is still poor. We demonstrated that somatic mutations associated with expansion of hematopoietic cells (“clonal haematopoiesis“ (CH)) are associated with a poor prognosis of patients with aortic valve stenosis undergoing TAVR. This application aims to address the following major points. We will determine 1) how mutations in the most prevalent CH-driver gene DNMT3A may directly or indirectly affect the pathophysiological processes leading to aortic valve stenosis, and 2) which type of mutation is particularly involved in mediating the poor prognosis. 3) We will determine the impact of CH on the reversibility of cardiac fibrosis after successful replacement of the aortic valve, and 4) determine the relation of CH with senescence and inflammaging. We will use cutting edge single cell and omics technologies to decipher the pathophysiological effects in patient tissues and circulating blood samples and will explore the pathomechanisms induced by DNMT3A CH-driver mutation by assessing cellular communication processes in vitro. The discovery of relevant of immune system mediated complexities in the progression of aortic valve stenosis and consequent cardiac fibrosis is expected to identify biomarkers and possible novel therapeutic targets to specifically intervene in patients with a high risk for worse outcome.