NOVEL MECHANISMS AND THERAPEUTIC APPROACHES TO IMMUNO-INFLAMMATORY LONG OT SYNDROME

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Recent evidence show that patient with autoimmune and inflammatory disorders have high circulating levels of both anti-Ro antibodies (Abs) and interleukin 6 (IL-6) both of which are associated with prolongation of corrected QT interval (QTc) on ECG. In this renewal application, we will test the overall hypothesis that anti-Ro Abs and IL-6 will inhibit the delayed rectifier HERG-K channel thus accounting for the clinical QTc prolongation and predisposition to cardiac arrhythmias. During the last funding period, we established a guinea-pig animal model for anti-Ro Abs associated QTc prolongation and provided the molecular and functional basis for this QTc prolongation. We showed that anti-Ro Abs prolong cardiomyocyte action potential by direct block of HERG channel at the pore region. Here, we will use state of the art 3D modeling to design a therapeutic biologic peptide that will compete with anti-Ro Abs on the HERG channel and thus prevent or reverse QTc prolongation. Furthermore, we will dissect the signaling pathways activated by IL-6 binding to its receptor to explain the QTc prolongation seen in patients with high IL-6 levels. Finally, we will investigate the molecular mechanisms by which IL-6 inhibits IKr. 3D-modeling of biologic peptides, electrophysiological and biochemical techniques will be applied to in-vivo guinea pigs, native cardiomyocytes and heterologous expression systems. Significance: Autoimmune and inflammatory disorders are associated with cardiovascular comorbidities and are increasingly recognized as a major health problem with prevalence continuously increasing especially in elderly Veterans. The findings from this application will provide novel mechanistic and therapeutic approaches to autoimmune- inflammatory associated QTc prolongation.