BPS2025 - De-orphanization of ABCC6 by metabolic crude-extract screening

Vascular calcification (VC) is a significant contributor to cardiovascular diseases, particularly in aging populations and patients with type II diabetes or chronic kidney disease. Despite its prevalence, effective treatments for VC remain limited due to a lack of understanding of its molecular mechanisms, leading to high rates of cardiovascular morbidity and mortality worldwide. We aim to advance the search for treatment targets by investigating pathogenic mutations in the ABCC6 transporter leading to the mineralization disorder pseudoxanthoma elasticum (PXE). ABCC6 is proposed to release a potent anti-calcification factor into circulation, but the identity of this factor remains ambiguous To de-orphanize this orphan transporter, we leverage recent advances in plant transportomics to identify the substrate transported by ABCC6 that prevents calcification. By utilizing crude metabolite extracts as complex substrate mixtures and Xenopus laevis oocytes as a heterologous expression system, we will screen for substrate(s) of ABCC6. By identifying the substrate(s) of ABCC6 and characterizing the molecular mechanisms underlying PXE we will provide a broader understanding of vascular calcification and PXE potentially leading to development of novel therapeutic treatments.