This proposal describes a five-year mentored physician-scientist training program to characterize the mechanobiology of endothelial-to-mesenchymal transition (EndMT) in cardiovascular calcification. Cardiovascular calcification is a highly prevalent process whereby calcium mineral forms within the blood vessels and heart tissue, and its presence is associated with an increased risk of morbidity and mortality. Despite decades of research, there remains no effective medical therapy to treat this process. Recent work has implicated EndMT in cardiovascular calcification. EndMT describes the phenomenon whereby endothelial cells lining the lumen of the heart valves or blood vessels are stimulated to dedifferentiate into mesenchymal cells. Subsequently, these mesenchymal cells are capable of differentiating into various lineages, including the chondrogenic and osteogenic lineages that can promote calcification. While EndMT is a promising target for therapeutic intervention in cardiovascular calcification, characterizing the EndMT process in experimental studies can be challenging. Current methods to assess EndMT, such as genetic lineage tracing studies and immunostaining detection of endothelial and mesenchymal marker expression, are labor-, resource-, and time- intensive. Further, these methods are binary assessments of EndMT and do not capture an important aspect of the process ? its dynamic mechanical nature. Endothelial cells undergoing EndMT alter their cytoskeletal mechanics, detach from their neighboring cells, and migrate into the interstitial space. Thus, their mechanical properties, or ?mechanophenotype,? during EndMT are likely dynamic, but have not been previously explored. In this proposal, we outline our aims to characterize the mechanophenotypes of EndMT, with the hope of developing novel, high-throughput platforms to more rapidly identify possible therapeutic targets for EndMT- related disease, including cardiovascular calcification. Further, the accompanying mentored career development training plan will allow the candidate to develop the expertise needed to successfully complete this project and will provide him with the mentorship and support necessary to become a fully independent scientific investigator. In line with the strategic goals of the NHLBI, the aims of this proposal focus on: (1) elucidating our understanding of the pathobiology of EndMT and cardiovascular calcification, and (2) developing innovative new platforms to accelerate our ability to identify therapeutic targets for these processes, thereby advancing translational research.
Cardiovascular calcification is a highly prevalent process whereby bone mineral forms in the heart tissue and blood vessels, and it contributes to a number of debilitating cardiovascular diseases, including chronic heart failure and myocardial infarction. Recent work has implicated endothelial-to-mesenchymal transition (EndMT) in the development of cardiovascular calcification, but while agents targeting the EndMT process may be promising, the current assessments of EndMT have inherent limitations that impede our ability to efficiently evaluate the efficacies of investigative therapies. In this proposal, we aim to characterize a novel component of EndMT? its mechanical properties or ?mechanophenotype? ? with the goal of developing innovative platforms to investigate the mechanobiological mechanisms of EndMT, and to identify and test therapeutic targets for EndMT and cardiovascular calcification in a high-throughput, resource-efficient manner.
