Considerable disease variation exists across individuals with both inherited and acquired cardiomyopathies, suggesting that modifiers significantly alter the progression of these diseases. Even in related individuals carrying identical genetic mutations, pathological cardiac remodeling can be quite different. The identification of cardiomyopathy modifiers is highly important to understand how cardiomyocytes adapt to pathological stimuli and, ultimately, may lead to novel therapeutic targets. Adult mammalian cardiomyocytes respond to many different pathological stressors by developing cellular hypertrophy. Cardiomyocyte hypertrophy secondary to genetic mutations is increasingly recognized as a common cause of heart failure and sudden death in both adolescents and adults. We utilized multiple animal models to discover that glucocorticoid receptor (GR) signaling modifies cardiomyocyte hypertrophic signaling pathways. Importantly, analysis of heart tissue from humans with hypertrophic cardiomyopathy confirmed that dysregulated glucocorticoid receptor signaling is important in the pathogenesis of human disease. Based on these findings, we hypothesize that cell state specific glucocorticoid signaling modifies cardiomyocyte stress response pathways. To investigate this hypothesis we will perform the following specific aims:
Aim 1 : Define the contribution of GR transactivation and transrepression in regulating pathological cardiomyocyte responses.
Aim 2 : Determine the role of the GR chaperone FKBP5 in regulating the cardiomyocyte stress response.
Aim 3 : Define cardiomyocyte GR transcriptional co-regulators in basal and disease states. Once completed, these innovative studies will provide novel insights into how GR signaling modifies cardiomyocyte adaptation to pathological stimuli and will yield new treatment targets for both genetic and acquired cardiomyopathies. This is highly significant because currently there are limited treatment options available for these diseases.
Heart failure is a leading cause of death in the United States, and novel treatment options are required to treat this condition. We discovered that glucocorticoid signaling is abnormal in human cardiomyopathy tissue. The experiments outlined in this proposal will help us to understand how this signaling pathway affects the heart, and through better understanding, our research may yield new treatment options for patients suffering from cardiomyopathy and heart failure.
| Nixon, Benjamin R; Sebag, Sara C; Glennon, Michael S et al. (2018) Nuclear localized Raf1 isoform alters DNA-dependent protein kinase activity and the DNA damage response. FASEB J :fj201800336R |
