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

> **NIH VA I01** · VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN · 2020 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 9898265
- **Project number:** 5I01BX002137-07
- **Recipient organization:** VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
- **Principal Investigator:** Mohamed Boutjdir
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-10-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898265

## Citation

> US National Institutes of Health, RePORTER application 9898265, NOVEL MECHANISMS AND THERAPEUTIC APPROACHES TO IMMUNO-INFLAMMATORY LONG OT SYNDROME (5I01BX002137-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898265. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*