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

最近的证据表明，患有自身免疫性疾病和炎症性疾病的患者具有较高的 抗Ro抗体（Abs）和白细胞介素6（IL-6）两者的循环水平， 与ECG校正QT间期（QTc）延长相关。在这次更新中， 应用中，我们将测试抗Ro Ab和IL-6将抑制 延迟整流型HERG-K通道，从而解释临床QTc延长， 易患心律失常。在上一个资助期间，我们设立了一个 抗Ro Ab相关QTc延长的豚鼠动物模型，并提供了 QTc间期延长的分子和功能基础。我们发现抗Ro抗体 通过直接阻断HERG通道在孔区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， HERG通道上的抗Ro Ab，从而预防或逆转QTc延长。此外，委员会认为， 我们将剖析IL-6与其受体结合激活的信号通路，以解释 在IL-6水平较高的患者中观察到QTc延长。最后，我们将研究分子 IL-6抑制IKr的机制。生物肽的3D建模，电生理学 生物化学技术将应用于体内豚鼠，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是 与心血管合并症相关，并且越来越多地被认为是一种主要的健康问题。 患病率不断增加的问题，特别是在老年退伍军人。这些发现 将提供新的机制和治疗方法， 炎症相关QTc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.