DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

Role of Iroquois transcription factors in cardiac arrhythmic diseases using induced pluripotent stem cells – HEART-iPS

Submission summary

Rationale: In western countries, cardiac arrhythmias affect more than 3% of the general population, causing high levels of morbidity and sudden cardiac death. In the heart, several transcription factors are powerful regulators of cardiac cell fate and organogenesis. Less well studied are the roles of transcription factors in physiological functions, such as the functional specialization of the ventricular conduction system or the sequence of ventricular electrical activity. These functions are intimately linked to the proper regulation of more than 100 ion channel subunits. Changes in their expression or function in the context of congenital or acquired heart disease affect action potentials and are likely to be at the root of cardiac arrhythmias and sudden death.

Objective: To understand role of Iroquois transcription factors (IRX) in the control of generation and propagation of cardiac electrical impulse.

Methods: To test our hypothesis, we will take advantage of a newly described rare congenital disorder, the Hamamy syndrome. Importantly, Hamamy patients carry a mutation in IRX5 gene and are characterized by both cardiac structural and electrophysiological defects, suggesting that the origin of some life-threatening arrhythmias, that usually develop as a patient ages, lies in cardiac structural and electrophysiological development. Therefore, studying the pathophysiological mechanism of this disease and the role of IRX5 may bring information to the mechanism of arrhythmias in the adult.
Studies have also suggested a role for IRX5 in another familial and more frequent arrhythmic disease, the Brugada syndrome, as it is associated with defects in ventricular repolarizing gradient which regulation is ensured by Irx5 in the mouse. However, this role has not been proven yet.
To do so, we designed a multidisciplinary experimental plan using biochemical, molecular and in vivo analyses with the following specific aims:
- Identifying the role of IRX5 transcription factor in human heart formation and function, through Hamamy syndrome modeling using iPS cells and transgenic mouse model.
- Exploring the role of IRX5 in the pathophysiology of Brugada syndrome using iPS cells.

Expected results: With this research project, using a combination of newly generated patient-derived iPS cells and transgenic mouse lines we will elucidate the functional role of IRX5 transcription factor in human cardiac physiology, and decipher its role in the abnormal cardiac phenotype of the Hamamy and Brugada syndromes.

Project coordination

Nathalie Gaborit (l'institut du thorax)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


INSERM UMR 1087 / CNRS UMR 6291 l'institut du thorax

Help of the ANR 272,988 euros
Beginning and duration of the scientific project: September 2015 - 36 Months

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