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

最近的证据表明，自身免疫性和炎症性疾病的患者有很高的 循环中抗Ro抗体(Abs)和白介素6(IL-6)水平 与心电图上校正的QT间期延长有关。在这次更新中 应用中，我们将检验抗Ro单抗和IL-6将抑制 延迟整流HERG-K通道可解释临床QT间期延长和 易患心律失常。在上一个资助期内，我们成立了一个 抗Ro单抗相关QT间期延长的豚鼠动物模型 QT间期延长的分子和功能基础。我们发现抗Ro抗体延长了 在孔区直接阻断HERG通道的心肌细胞动作电位。在这里，我们将 使用最先进的3D建模来设计一种治疗性生物肽，它将与 在HERG通道上产生抗Ro抗体，从而阻止或逆转QT间期延长。此外， 我们将剖析IL-6与其受体结合激活的信号通路，以解释 IL-6水平高的患者QTC延长。最后，我们将研究分子 IL-6抑制IKR的机制。生物多肽、电生理学的三维建模 生化技术将应用于活体豚鼠、天然心肌细胞和 异源表达系统。意义：自身免疫性和炎症性疾病 与心血管合并症有关，并日益被认为是一种主要健康 患病率持续上升的问题，特别是在老年退伍军人中。调查结果 将为自身免疫提供新的机制和治疗方法- 炎症性QT间期延长。

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.