Inducing Cardiomyocyte Replacement in Congenital Heart Disease

The goal of this project is to develop new therapies to stimulate heart muscle growth and regeneration in humans. Our strategy is to use administration of the extracellular growth factor neuregulin to stimulate heart muscle cell proliferation. Our translational work is advancing toward preparations for a clinical trial of administration of recombinant neuregulin in pediatric patients with heart disease. Since the neuregulin receptors, the receptor tyrosine kinases ErbB2, ErbB3, and ErbB4, are also expressed in the central nervous system, it is possible that administration of recombinant neuregulin may affect CNS function. This provides an opportunity to examine the effect of modulating the neuregulin/ErbB complex on CNS function. The neuregulin/ErbB complex has been connected to schizophrenia using human molecular genetics and animal studies (Corfas et al., Nat. Neurosci. 2004). Recent studies have shown that the timing of modulation of the activity of the neuregulin/ErbB complex matters greatly for the development of schizophrenia-like symptoms in mice (Yin et al., Neuron 2013). Most striking was the finding that even post-natal activation of ErbB4 in the CNS induced schizophrenia-like symptoms, which were reversible. An additional important connection between this project and the IDDRC mission is the relationship between congenital heart disease and developmental disability. This relationship has been demonstrated by Jane Newburger at our center and by others. Thus, in addition to a direct effect on the heart, administration of recombinant neuregulin may modulate the CNS dysfunction in patients with congenital heart disease. In this project, we will administer recombinant neuregulin in mice of different ages and with and without experimentally induced heart disease. We will examine the effect on cognitive function using the IDDRC Neurobehavioral core. The results will provide significant information for the design of future clinical trials of administration of recombinant neuregulin in infants and children with heart disease.