Recognition of O-GlcNAc Modified Proteins Using Site-Specific Antibodies

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Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery) for no apparent reason. PAH is a disease of pulmonary vascular endothelial dysfunction with nitric oxide (NO) deficiency and dysregulated glucose metabolism/utilization. It is a heterogeneous disorder likely to be comprised of overlapping syndromes with varying origins and pathobiologies that presents with many phenotypes. The idiopathic form of pulmonary arterial hypertension (IPAH) is progressive and results in the deterioration of cardiopulmonary function and premature death. The mean age at diagnosis of IPAH is 50 years with a higher female to male ratio. Presently, PAH is considered a vasculopathy, and metabolic dysregulation has emerged as a major area of research in the pathobiology of the disease. These metabolic changes results in structural and morphological changes within the lung vasculature and cause increased pulmonary artery pressure and pulmonary vascular resistance, which lead to right ventricular failure. Our lab and others have shown that IPAH patients exhibit altered levels of NO, O-GlcNAc, glucose metabolism, and insulin resistance. The nature of the primary abnormalities that trigger and perpetuate these characteristics remains unclear. Currently, all therapies in PAH target vasodilators and vasoconstrictors pathways (e.g. NO deficiency). The future of IPAH therapies depend on our ability to identify the new molecular targets within these pathways. However, the tools available to understand the role of glycosylation in human health and disease are lacking. In particular, highly specific antibodies that can recognize peptide specific sequences modified by O-GlcNAc is needed to help us better understand the disease pathobiology and improve treatment of pathologic phenotypes in IPAH. Here we propose to create the first antibodies to allow the study researchers to investigate the role of O-GlcNAc in PAH. We anticipate that these antibodies will help shed light on PAH disease mechanism(s), and potentially offer new therapeutic approaches.