My research program stems from the discovery of the rare monogenetic disease, Arterial Calcification due to Deficiency of CD73 (ACDC; OMIM #211800). Patients with ACDC have a history of cramping pain in their calves, thighs, and buttocks. They have chronic ischemic pain in their feet, and can only walk a short distance before discomfort compels them to stop. Imaging and pathological studies showed extensive calcification in their lower-extremity arteries, localized to the medial layer (Figs. 1 & 2). Additionally, a pathological study of an ACDC patient vessel showed evidence of medial dysplasia, stenosis, and arteriomegaly. The phenotypes in ACDC are shared in a handful of more common diseases and disorders, which highlights the importance of using insights gained from rare genetic diseases as a means to identify new genotype-to-phenotype relationships that are often hard to pinpoint in common disease pathologies. Patients with ACDC harbor genetic mutations in the gene 5’-ectonucleotidase, which encodes for the protein CD73. CD73 is an enzyme that acts one step downstream of enzymes ENPP1 and CD39 in extracellular ATP metabolism, converting AMP to adenosine (Fig. 3). The mutations identified in ACDC patients result in loss of CD73 enzymatic activity, diminishing extracellular adenosine production. Adenosine acts as a signaling molecule in a variety of cellular processes via binding adenosine receptors (A1, A2a, A2b, and A3). Adenosine is described as a “retaliatory metabolite” as it is generated extracellularly in response to stresses like shear flow, mechanical stress, inflammation, and hypoxia, and has been found to elicit protective responses to these adverse conditions in the vasculature. These stresses are continuously present in vessels, and the release and breakdown of ATP to adenosine activates pathways that allow cells to adapt to these stresses. Our general hypothesis is that the deleterious phenotypes in ACDC vasculature occur due to a lack of adenosine signaling. Supporting this postulation, our in vitro disease model shows that lack of CD73 results in calcification, which is reversed with genetic rescue, and significantly reduced with exogenous adenosine treatment (Fig. 4). This discovery is the first to link adenosine and ectopic calcification. Research conducted in my lab will explore the role of CD73 and adenosine signaling in complex vascular pathologies in vitro (primary human and mouse cells and patient-specific induced-pluripotent stem cells) and in vivo (genetically defined murine models and surgical manipulations), with the goal of translating our findings in ACDC to more common vascular diseases and pathologies.