CONDITIONAL LINEAGE ABLATION TO MODEL HUMAN-DISEASES

Cell loss contributes to the pathogenesis of many inherited and acquir ed human diseases, We have developed a system to conditionally ablate cells of any lineage and developmental stage in the mouse by regulated expression of the diphtheria toxin A (DTA) gene by using tetracycline -responsive promoters. As an example of this approach, we targeted exp ression of DTA to the hearts of adult mice to model structural abnorma lities commonly observed in human cardiomyopathies. Induction of DTA e xpression resulted in cell loss, fibrosis, and chamber dilatation. As in many human cardiomyopathies, transgenic mice developed spontaneous arrhythmias in vivo, and programmed electrical stimulation of isolated -perfused transgenic hearts demonstrated a strikingly high incidence o f spontaneous and inducible ventricular tachycardia. Affected mice sho wed marked perturbations of cardiac gap junction channel expression an d localization, including a subset with disorganized epicardial activa tion patterns as revealed by optical action potential mapping. These s tudies provide important insights into mechanisms of arrhythmogenesis and suggest that conditional lineage ablation may have wide applicabil ity for studies of disease pathogenesis.