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

免疫炎症性长 OT 综合征的新机制和治疗方法

基本信息

批准号：
10265378
负责人：
Mohamed Boutjdir
金额：
--
依托单位：
VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265378
关键词：
Accounting Action Potentials Animal Model Antibodies Antidepressive Agents Antipsychotic Agents Arrhythmia Autoimmune Autoimmune Diseases Binding Biochemical Biological Biological Models Biological Response Modifier Therapy Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cavia Cells Clinical Clinical Data Data Development Disease Dose Elderly Electrocardiogram Electrophysiology (science)Epitopes Funding Health Heart Abnormalities High Prevalence Homology Modeling IL-6 inhibitor Immunize Incidence Inflammatory Interleukin-6 Life Molecular Molecular Conformation Morbidity - disease rate Muscle Cells Pathogenicity Pathway interactions Patients Peptides Pharmacology Potassium Channel Predisposition Prevalence Protein Engineering Reporting Risk Risk Factors Role SS-A antibodies SS-A antigen Signal Pathway Syndrome System Techniques Testing Therapeutic Time Torsades de Pointes Ventricular Veterans Woman Work base comorbidity cross reactivity design extracellular heart rhythm in vivo men mimicry mortality novel novel therapeutics prevent receptor sudden cardiac death three dimensional structure three-dimensional modeling

项目摘要

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.

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) 的循环水平均为与心电图校正 QT 间期 (QTc) 的延长有关。在这次更新中应用程序中，我们将测试抗 Ro Abs 和 IL-6 将抑制的总体假设延迟整流 HERG-K 通道从而解释了临床 QTc 延长和心律失常的倾向。在上一个资助期间，我们建立了一个抗 Ro Abs 相关 QTc 延长的豚鼠动物模型，并提供了 QTc 延长的分子和功能基础。我们证明抗 Ro Abs 可以延长通过直接阻断孔区域的 HERG 通道来调节心肌细胞动作电位。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，该肽将与 HERG 通道上的抗 Ro 抗体，从而防止或逆转 QTc 延长。此外，我们将剖析 IL-6 与其受体结合激活的信号通路来解释 IL-6 水平高的患者出现 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、电生理学生化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：自身免疫性疾病和炎症性疾病是与心血管合并症相关，并且越来越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中。研究结果该应用将为自身免疫性疾病提供新的机制和治疗方法炎症相关的 QTc 延长。