COREGULATORY MECHANISMS OF CELLULAR RECRUITMENT IN FIBROCALCIFIC AORTIC VALVE DISEASE Terence William Gee, Ph. D. Cornell University 2020 The objective of this thesis was to develop and implement in vitro and in vivo model systems to understand complex, collaborative cellular mechanisms underpinning calcific aortic valve disease, an increasingly prevalent cardiovascular pathology lacking effective early diagnostic and therapeutic strategies save for invasive prosthetic replacement surgery. Through this work we have identified the role for canonical NF_B functioning as a “gatekeeper” for valve endothelial cell initiation and active participation in degenerative tissue calcification and identified this pathway as a promising therapeutic target for further preclinical evaluation. We further developed an in vitro platform through which cocultured endothelial and interstitial cells develop emergent, macro-calcific lesion features with underlying cellular and molecular signaling features recapitulative of the human etiology. Through these respective works we identify a subpopulation of endothelial derived mesenchymal progenitors, likely derived via post-natal reactivation of the Endothelial-to-Mesenchymal Transformation process, as being crucial role-players of the pathogenic process. Lastly, we build upon these systems to interrogate the diverse role of the Notch cell-fate decision making pathway in regulating valvular cell calcific transformation and matrix remodeling activity. The hope is that from the knowledge gleaned from this work, and by establishing these model systems, we can better understand the pathobiology of this and identify effective diagnostic markers for the disease or therapeutic candidates for its treatment.