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：
9898265
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/9898265
关键词：
Accounting Action Potentials Animal Model Antibodies Antidepressive Agents Antipsychotic Agents Arrhythmia Autoimmune Diseases Autoimmune Process 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 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，自身免疫性和炎症性疾病的患者患有较高抗RO抗体（ABS）和白介素6（IL-6）的循环水平均为与ECG上校正的QT间隔（QTC）延长有关。在此续约中应用，我们将测试抗ABS和IL-6的总体假设延迟整流器HERG-K渠道，因此考虑了临床QTC延长和心律不齐的易感性。在最后一个资金期间，我们建立了一个用于抗罗ABS相关的QTC延长的豚鼠动物模型，并提供了该QTC延长的分子和功能基础。我们证明了抗抗ABS延长孔区域HERG通道的直接阻滞的心肌细胞动作潜力。在这里，我们会的使用艺术3D建模的状态设计将与 HERG通道上的抗抗ABS，从而预防或反向QTC延长。此外，我们将通过IL-6与其受体结合激活的信号传导途径，以解释 QTC延长在高IL-6水平的患者中可见。最后，我们将研究分子 IL-6抑制IKR的机制。生物学肽，电生理学的3D模型并将生化技术应用于体内豚鼠，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有关，并越来越被认为是主要健康状况患病率的问题不断增加，尤其是在老年退伍军人中。发现从该应用中，将提供新型的机械和治疗方法来自身免疫性炎症相关的QTC延长。